Note: Descriptions are shown in the official language in which they were submitted.
CA 02673485 2009-06-19
Description
GASTRIC RETENTION-TYPE SUSTAINED-RELEASE LEVODOPA
PREPARATION
TECHNICAL FIELD
[0001]
The present invention relates to a gastric
retention-type sustained-release levodopa preparation. More
specifically, the invention relates to a gastric
retention-type sustained-release levodopa preparation by
which levodopa is persistently delivered to upper area of the
small intestine which is an absorptive site for levodopa.
BACKGROUND ART
[0002]
Parkinson's disease is a chronic and progressive nerve
disease showing ataxic symptoms including tremor, rigidity,
dullness, postural reflex disturbance and gait disturbance.
Although the causes therefor have not been clarified yet, it
is likely that nigrostriatal dopamine-producing cells are
fallen off in a gradually progressive manner.
[0003]
Levodopa is a basic therapeutic agent for treating
Parkinson's disease. Since levodopa is promptly metabolized
by dopa decarboxylase, etc., it is sometimes necessary to
ingest the dose of as high as 2 to 3 g and adverse actions such
as nausea, vomiturition or palpitation are apt to happen.
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[0004]
Further, in patients suffering from Parkinson's disease,
a wearing-off phenomenon or an on-off phenomenon where the
effect of the drug often lowers and becomes gradually unstable
often happens whereby it is necessary that levodopa is
persistently administered.
[0005]
In order to suppress the metabolism of levodopa so as
to express the stable effect and to reduce the adverse action,
a composite preparation comprising dopa and a dopa
decarboxylase inhibitor which suppresses the dopa
decarboxylation reaction and/or catechol-0-methyltransferase
inhibitor which suppresses methylation of dopa has been
developed.
[0006]
Incidentally, in levodopa, its half-life in blood is as
short as 60 to 90 minutes and it is mostly absorbed from the
upper area of the small intestine whereby it is preferred to
prepare a dosage form where levodopa is continuously delivered
to the upper area of the small intestine. As to the preparation
suitable for such an object, gastric retentive preparations
of a mucosa-adhesion type, a unique-shape type, a swelling type
and a floating type have been developed.
[0007]
The gastric retentive preparation of a mucosa-adhesion
type is intended to prolong the gastric residence time by
inclusion therein of a mucosa-adherent substance that allows
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the preparation to adhere to the mucosa of the stomach. However,
the preparation is unable to provide a sufficient gastric
residence time because it does not readily adhere to the wall
of a rapidly moving stomach and readily detaches itself from
the mucosa by the metabolic turnover of the mucosa. There is
also a problem of safety, such as a concern over the irritant
effect of the preparation on the stomach mucosa.
[0008]
The gastric retentive preparation of a unique-shape type
is designed to elongate and extend at a particular temperature,
pH or other conditions of the stomach environment so that it
takes the unique shape of, for example, crossed rods or a
windmill that permits the gastric retention. However, owing
to the unique shape, the preparation is difficult to achieve
and has the risk of damaging the -stomach mucosa or preventing
passage of food.
[0009]
The gastric retentive preparation of a swelling type is
intended to extend the gastric residence time with the use of
an ingredient that swells upon contact with water and thereby
increases the preparation to a size that makes passage through
the pylorus difficult.
[0010]
However, in the gastric retentive preparation of a
swelling type, the attempt to prevent passage through the
pylorus is made by increasing the size of preparation, which
is achieved by the swelling of the preparation. Because of
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this, the preparation intrinsically lacks the mechanical
strength necessary to resist the mechanical movement, such as
contraction, of the stomach. Therefore, the preparation, when
swollen, readily undergoes erosion and reduces its size.
Further, because release of a drug is controlled by the erosion
of the preparation, control of drug release is difficult when
the preparation is designed to erode slowly, whereas, when
designed to erode quickly the preparation reduces its size and
is easily expelled from the stomach. For this reason, the
gastric retentive preparation of a swelling type is greater
in size than other types of gastric retentive preparations,
which makes the preparation difficult to ingest.
[0011]
Recently, a gastric retentive preparation of a swelling
type has been reported in which the bilayer structure formed
of a drug layer and a swelling layer containing an ingredient
selected from xanthan gum, guar gum, hydroxypropyl methyl
cellulose, polyvinyl alcohol and gum arabic allows the drug
releasing property and the swelling property to be
independently controlled (see Patent literature 1) . However,
assessment of the preparation by the inventors of the present
invention revealed that the preparation still had the
conventional problem; namely, the preparation has poor
mechanical strength after swelling and readily undergoes
erosion, and cannot provide a sufficient gastric residence time
when it has an easily ingestible size, whereas ingestion is
difficult when the preparation is designed to provide a
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sufficient gastric residence time.
[0012]
There has been also a report of a preparation in which
a portion of a polymer matrix that swells upon contact with
the gastric fluid is surrounded by a band which is prepared
from an insoluble substance such as polyethylene, polystyrene,
ethylene-vinyl acetate copolymer or polycaprolactone that
prevents the covered portion of the polymer matrix from
swelling and thereby provides sufficient rigidity (mechanical
strength) to withstand stomach contractions and delay
expulsion of the preparation from the stomach (see Patent
Publication 2) . However, complicated procedures are required
to surround a portion of the polymer matrix with the band, and
preparation of such preparations on industrial scale is
difficult to achieve.
[0013]
The gastric retentive preparation of a floating type is
intended to extend the gastric residence time by causing the
preparation to float in the stomach. However, because it takes
time before the orally administered preparation floats, there
are cases where the preparation is expelled from the stomach
before it can float in the stomach.
[0014]
To solve this problem, a gastric retentive preparation
of a floating type has been proposed that has a bilayer
structure including a layer formed of a pharmaceutical additive
of a low bulk density (floating layer) and a drug-release
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control layer (see Patent literature 2) The floating layer
of the preparation includes a low-density high-bulk cellulose
derivative such as ethyl cellulose and provides a sufficient
gastric residence time. However, since most of the floating
layer is not eroded in the body, there is a problem that the
digestive tract may be damaged, among others. Further, since
the floating layer is excreted with the feces in its original
form, it may give patients an uneasy feeling.
[0015]
As to a sustained-release levodopa preparation or a
combination preparation of levodopa with carbidopa, there is,
for example, Sinemet CR (trade mark) sold in the United States
and it releases levodopa and carbidopa during 4 to 6 hours by
erosion of the polymer.
[0016]
Patent literature 3 discloses a combination preparation
of levodopa with carbidopa which is a controlled release orally
administering prescription preparation containing
hydroxypropyl cellulose which is a water-soluble polymer and
vinyl acetate-crotonic acid copolymer which is less
water-soluble polymer.
[0017]
Patent literature 4 discloses a combination preparation
of levodopa with carbidopa comprising a sustained release
central core containing cellulose ether and microcrystalline
cellulose and an outer layer having a releasing property of
a medium degree.
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[0018]
Patent literature 5 discloses a gastric retentive
combination preparation of levodopa with carbidopa of a
swelling type containing hydrogel such as hydroxypropyl methyl
cellulose or hydroxypropyl cellulose; an ultra-disintegrating
agent selected from the group consisting of cross-linked
carboxymethyl cellulose sodium, starch-sodium glycolate and
cross-linked polyvinylpyrrolidone; and tannin.
[0019]
Patent literature 6 discloses a gastric retentive
combination preparation of levodopa with carbidopa of a
floating type comprising a swelling membrane containing a
binder selected from the group consisting of polyoxyethylene
stearate, poloxamer, polyethylene glycol, glycerol
palmitostearate, glyceryl monostearate, methyl cellulose and
polyvinylpyrrolidone; a gas-generating agent selected from
the group consisting of sodium bicarbonate, sodium carbonate,
glycine-sodium carbonate, potassium carbonate, calcium
carbonate, magnesium carbonate and a mixture thereof; and
polyvinyl alcohol.
[0020]
Nonpatent literature 1 discloses a gastric retentive
preparation of levodopa in which a preparation in a sheet shape
containing (1) hydrolyzed gelatin, L-polylactic acid and ethyl
cellulose or (2) Eudragit L (trade name) and ethyl cellulose
is folded and sealed into a capsule and, after administration,
the folded sheet-shaped preparation opens in the stomach
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whereby the preparation is retained in the stomach.
Patent literature 1: JP-A-2005-132803
Patent literature 2: International Publication Pamphlet WO
99/07342
Patent literature 3: JP-T-06-67830 (the term "JP-T" as used
herein means a published Japanese translation of a PCT patent
application)
Patent literature 4: International Publication Pamphlet WO
2000/15197
Patent literature 5: International Publication Pamphlet WO
2002/000213
Patent literature 6: International Publication Pamphlet WO
2004/032906
Nonpatent literature 1: Klausner, E. A., et al. Pharmaceutical
Research, 2003, Vol. 20, No. 9, pages 1466 to 1473
DISCLOSURE OF THE INVENTION
[0021]
An object of the present invention is to provide a
levodopa preparation in an easily ingestible size being able
to release levodopa sustainedly in the stomach.
[0022]
The inventors of the present invention diligently worked
and found that, in the preparations in the same size, discharge
from the stomach is better when the mechanical strength is lower
and that the above problems are able to be solved by the use
of a gastric retentive layer being unclassified into any of
known categories that has sufficient retentive properties
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owing to a high mechanical strength in the stomach and has
desirable disintegrating properties in the intestinal tract
and accomplished the present invention.
[0023]
Thus, the gist of the present invention lies in a gastric
retentive preparation including a gastric resident layer and
a drug releasing layer containing levodopa as a medicament,
wherein the gastric resident layer contains a polymer
ingredient which shows high solubility or swelling property
in a weakly acidic or a weakly alkaline medium than in an acidic
medium.
ADVANTAGEOUS EFFECTS OF THE INVENTION
[0024]
The gastric retentive preparation in accordance with the
present invention retains in the stomach for long time and
continues in releasing levodopa whereby it is able to well
retain the concentration of levodopa in blood.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025]
[Fig. 1] Fig.1 shows a diagram illustrating an apparatus
used for strength test.
[Fig. 2] Fig.2 shows a diagram illustrating the changes in
concentration of levodopa in blood, in which the vertical axis
represents concentration and the horizontal axis represents
time.
[Fig. 3] Fig.3 shows a diagram illustrating the changes in
concentration of levodopa in blood, in which the vertical axis
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represents concentration and the horizontal axis represents
time.
[Fig. 4] Fig.4 shows the dissolution rate of levodopa from
the preparation of Example 7.
[Fig. 5] Fig.5 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 1.
[Fig. 6] Fig.6 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 3.
[Fig. 7] Fig.7 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 4.
[Fig. 8] Fig.8 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 5.
[Fig. 9] Fig.9 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 6.
[Fig. 10] Fig.10 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 8.
[Fig. 11] Fig.11 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 9.
[Fig. 12] Fig.12 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 10.
[Fig. 13] Fig.13 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 11.
[Fig. 14] Fig.14 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 12.
[Fig. 15] Fig.15 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 13.
[Fig. 16] Fig.16 shows the dissolution rate of
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levodopa-carbidopa from the preparation of Example 14.
[Fig. 17] Fig.17 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 15.
[Fig. 18] Fig.18 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 16.
[Fig. 19] Fig.19 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 17.
[Fig. 20] Fig.20 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 18.
[Fig. 21] Fig.21 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 19.
[Fig. 22] Fig.22 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 20.
[Fig. 23] Fig.23 shows the dissolution rate of
levodopa-carbidopa from the preparation of Example 21.
BEST MODE FOR CARRYING OUT THE INVENTION
[0026]
A gastric retentive preparation containing levodopa of
the present invention comprises a gastric resident layer and
a drug releasing layer, wherein the gastric resident layer does
not disintegrate in the stomach and disintegrates in the
intestinal tract.
[0027]
As used herein, the term "does not disintegrate in the
stomach" means that the gastric resident layer is not eroded
by the gastric fluid or the contraction motion of the stomach
and the shape thereof remains stable. The gastric retentive
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preparation having the gastric resident layer that does not
disintegrate in the stomach is, for example, one in which the
gastric resident layer has the shortest diameter (hereinafter
referred to as "small diameter") of 7 mm or more, and more
preferably 8 mm or more, which makes passages through the
pylorus difficult, as measured after stirring the preparation
in the first fluid at 200 rpm at 37 C for 15 hours under the
conditions of the paddle method in the dissolution test in
accordance with the Japanese Pharmacopoeia, Fourteenth
Edition (hereinafter referred to as "JP").
[0028]
Preferably, the preparation has mechanical strength
against the mechanical action such as the contraction motion
of the stomach, because the preparation is subjected to such
action in the stomach in addition to the erosion by the gastric
fluid. An example of a preparation with mechanical strength
is one that can retain its shape in a test simulating the
mechanical action of the stomach, or more specifically one that
has a maximum load of 5000 g or more when compressed by 60 mm
per minute to a thickness of 1 mm after being rotated at 200
rpm at 37 C for 10 hours in a horizontally laid 50 mL volume
conical tube (30 x 115 mm) containing 50 g of glass beads having
an outer diameter of about 4 mm to 5 mm and 30 mL of the JP
first fluid, the JP first fluid being replaced eVery 2. 5 hours
during the rotation. A preparation with a maximum load below
5000 g is apt to be discharged from the stomach and readily
undergoes erosion and, therefore, it may reduce to a size small
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enough to pass through the pylorus. It is therefore preferable
that the preparation has a maximum load of 10000 g or more.
The preparation after the test preferably has a small diameter
of 7 mm or more, and more preferably 8 mm or more, which makes
passage through the pylorus difficult.
[0029]
The term "disintegrates in the intestinal tract" means
that the gastric resident layer quickly disintegrates in the
intestinal fluid. An example of a gastric resident layer that
disintegrates in the intestinal tract is one that has a maximum
diameter (hereinafter referred to as "large diameter") of 6
mm or less as measured after the preparation, taken out of the
first fluid in which the preparation had been stirred under
the conditions of the paddle method in the dissolution test
in accordance with the JP was stirred in the second fluid at
200 rpm at 37 C for 9 hours under the same conditions. It can
be said that the preparation has better disintegrating
properties when the gastric resident layer has smaller large
diameters after the test. It is therefore preferable that the
preparation has a large diameter of 4 mm or less, and
particularly 2 mm or less. A preparation with the gastric
resident layer that completely disintegrates is most
preferable.
[0030]
The gastric resident layer of the gastric retentive
preparation contains a polymer ingredient (hereinafter
referred to as "pH-dependent polymer ingredient") which shows
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higher solubility or swellability in a weakly acidic to weakly
alkaline medium such as intestinal fluid (pH 5 to 8) than in
an acidic medium such as gastric fluid (pH 1 to 3) whereby it
is now possible to make a preparation which does not
disintegrate in the stomach but disintegrates in the intestinal
tract.
[0031]
The pH-dependent polymer ingredient may be an enteric
ingredient and/or a polymer ingredient selected from the group
consisting of carboxymethyl cellulose, polyacrylic acids and
polysaccharides having a carboxyl group or a sulfo group
(hereinafter such a polymer ingredient will be referred to as
"acidic functional group-containing polymer ingredient").
[0032]
Any enteric ingredient may be used so far as it is a
substance commonly used for enteric preparations and that
dissolves or swells in an aqueous solution at a pH of 5.5 or
higher. For example, the enteric ingredient may be enteric
cellulose derivatives such as cellulose acetate phthalate,
cellulose acetate succinate, methyl cellulose phthalate,
hydroxymethyl ethyl cellulose phthalate, hydroxypropyl methyl
cellulose phthalate, hydroxypropyl methyl cellulose acetate
succinate, cellulose acetate trimellitate or carboxymethyl
ethyl cellulose; enteric acrylic acid copolymers such as a
methyl methacrylate-methacrylic acid copolymer, a
styrene-acrylic acid copolymer, a methyl acrylate-methacrylic
acid-octyl acrylate copolymer, a methacrylic acid-ethyl
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acrylate copolymer (Eudragit L 100-55 and Eudragit L 30D-55,
trade mark), a methyl acrylate-methyl
methacrylate-methacrylic acid copolymer (Eudragit FS 30D,
trade mark) or a methacrylic acid-methyl methacrylate
copolymer (Eudragit L 100 and Eudragit S 100, trade mark);
enteric polyvinyl derivatives such as polyvinyl butyrate
phthalate or polyvinyl acetoacetal phthalate; and enteric
maleic acid-vinyl copolymers such as a copolymer of vinyl
acetate and maleic acid anhydride, a copolymer of vinyl butyl
ether and maleic acid anhydride or a copolymer of styrene and
maleic acid monoester. Among these, the enteric cellulose
derivatives and enteric acrylic acid copolymers are preferable.
The enteric ingredient may be used either individually or in
a combination of two or more kinds with any proportions.
[0033]
When an enteric ingredient is used as a pH-dependent
polymer ingredient, the amount of the enteric ingredient in
the gastric resident layer is usually not less than 50% by
weight, preferably not less than 60% by weight, more preferably
not less than 70% by weight and, still more preferably, not
less than 80% by weight of the gastric resident layer.
[0034]
Examples of carboxymethyl cellulose include carmellose,
carmellose calcium, carmellose sodium, and croscarmellose
sodium. Examples of polyacrylic acids include carboxyvinyl
polymer and polycarbophil calcium. Examples of
polysaccharides having a carboxyl group or a sulfo group
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include sodium carboxymethyl starch, alginic acid, xanthan gum,
gellan gum, hyaluronic acid, carrageenan, chondroitin sulfate
and dextran sulfate. Among these, the carboxymethyl
celluloses and polyacrylic acids are preferable. The acidic
functional group-containing polymer ingredient may be used
either individually or in a combination of two or more kinds
with any proportions, or in further combination with the
enteric ingredient.
[0035]
When an acidic functional group-containing polymer
ingredient is used as a pH-dependent polymer ingredient, the
amount of the acidic functional group-containing polymer
ingredient in the gastric resident layer is usually 1 to 50%
by weight, preferably 2 to 30% by weight and, more preferably,
3 to 20% by weight of the gastric resident layer.
[0036]
When solubility or swellability of the pH-dependent
polymer ingredient is high, there are cases where the gastric
retentive preparation readily disintegrates. Such tendency
is prominent when the acidic functional group-containing
polymer ingredient is used as an ingredient. In this case,
the gastric retentive preparation that retains its shape in
the stomach and shows a disintegrating property in the
intestinal tract can be realized by inclusion of a hydrophobic
ingredient that exhibits a moderate strength in water.
Examples of such a hydrophobic ingredient include: cellulose
derivatives such as ethyl cellulose or cellulose acetate;
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acrylic acid copolymers such as an ethyl acrylate-methyl
methacrylate copolymer (Eudragit NE; trade mark) or an ethyl
acrylate-methyl methacrylate-trimethylammonioethyl
methacrylate chloride copolymer (Eudragit RL and Eudragit RS;
trade marks); polyvinyl derivatives polymers such as an
ethylene-vinyl acetate copolymer or vinyl acetate resin; oils
and fats such as hydrogenated oil, whale wax, bee wax, carnauba
wax, lanolin or cacao buffer; higher fatty acids such as capric
acid, lauric acid, myristic acid, palmitic acid, stearic acid,
arachic acid or behenic acid; higher fatty acid esters such
as higher fatty acid alkyl esters, polyglycerol higher fatty
acid esters, higher fatty acid sorbitans, higher fatty acid
polyethylene glycols or sucrose higher fatty acid esters;
higher alcohols such as lauryl alcohol, myristyl alcohol, cetyl
alcohol, stearyl alcohol or behenyl alcohol; hydrocarbons such
as polyethylene, polystyrene, polyisobutylene or
microcrystalline wax; polycaprolactone; polylactate;
polyglycolate; and polyamides. Examples of higher fatty acid
alkyl esters include myristyl myristate, cetyl palmitate,
cholesteryl stearate and batyl monostearate. Examples of
polyglycerol higher fatty acid esters include glyceryl
myristate, glyceryl monostearate, glyceryl distearate,
diglyceyrl monostearate, tetraglceryl monostearate,
tetraglyceryl tristearate, tetraglceryl pentastearate,
hexaglyceryl monostearate, hexaglyceryl tristearate,
hexaglyceryl tetrabehenate, decaglyceryl monostearate,
decaglyceryl distearate, decaglyceryl tristearate,
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decaglyceryl pentastearate, decaglyceryl
pentahydroxystearate, decaglyceryl heptastearate and
decaglyceryl decastearate. Examples of higher fatty acid
sorbitans include sorbitan monopalmitate, sorbitan
monostearate, sorbitan sesquistearate and sorbitan
tristearate. Examples of higher fatty acid polyethylene
glycols include ethylene glycol monostearate, polyethylene
glycol monostearate, ethylene glycol distearate, diethylene
glycol stearate and polyethylene glycol distearate. Examples
of sucrose higher fatty acid esters include sucrose stearate
ester, sucrose palmitate ester, sucrose oleate ester, sucrose
laurate ester, sucrose behenate ester andsucrose erucate ester.
Among these, the cellulose derivatives or oils and fats are
preferable. The hydrophobic ingredient may be used either
individually or in a combination of two or more kinds with any
proportions.
[0037]
The proportions of the pH-dependent polymer ingredient
and the hydrophobic ingredient may be decided such that the
residence time in human is 12 hours or more and, preferably,
12 to 24 hours depending upon the types of the ingredients used
and that the gastric resident layer quickly disintegrates in
the intestinal tract. The hydrophobic ingredient is generally
in the range of 0 part by weight to 40 parts by weight, preferably
0 part by weight to 30 parts by weight and, particularly
preferably, 0 part by weight to 20 parts by weight, with respect
to 1 part by weight of the pH-dependent polymer ingredient in
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the gastric resident layer.
[0038]
When an acidic functional group-containing polymer
ingredient and hydrophobic ingredient are contained in the
gastric resident layer, the proportions of the acidic
functional group-containing polymer ingredient and the
hydrophobic ingredient may be decided such that the residence
time in human is 12 hours or longer or, preferably, 12 to 24
hours, depending on the types of the ingredients used and that
the gastric resident layer quickly disintegrates in the
intestinal tract. The hydrophobic ingredient is generally in
the range of 1 to 40 part (s) by weight, preferably 2 to 30 parts
by weight or, more preferably, 5 to 20 parts by weight with
respect to 1 part by weight of the acidic functional
group-containing polymer ingredient in the gastric resident
layer.
[0039]
By including a water-soluble ingredient in the gastric
resident layer with the pH-dependent polymer ingredient and
a necessary hydrophobic ingredient, the disintegrating
property of the gastric resident layer can be controlled to
adjust the gastric residence time and the ease of
disintegration in the intestinal tract. Examples of a
water-soluble ingredient include hydroxyalkyl celluloses such
as hydroxypropyl cellulose, hydroxypropylmethyl cellulose
(2208, 2906 and 2910) or hydroxyethyl cellulose; polyvinyl
derivatives such as povidone, crospovidone or polyvinyl
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alcohol; polyethylene oxides; methyl cellulose; gelatin;
polysaccharides such as pregelatinized starch, partially
pregelatinized starch, pullulan, dextrin, sodium alginate or
gum arabic; Macrogols such as Macrogol 400, Macrogol 1500,
Macrogol 4000, Macrogol 6000 or Macrogol 20000; sugars such
as lactose, saccharose, trehalose or glucose; and sugar
alcohols such as mannitol, xylitol, sorbitol, erythritol or
maltitol. Among these, hydroxyalkyl celluloses, polyvinyl
derivatives, polyethylene oxides, sugars or sugar alcohols are
preferred.
[0040]
The proportion of the water-soluble ingredient may be
appropriately decided such that the gastric residence time is
12 hours or longer or, preferably, 12 to 24 hours and that the
gastric resident layer quickly disintegrates in the intestinal
tract.
[0041]
In the case where the gastric resident layer containing
the enteric ingredient additionally contains the
water-soluble ingredient, the gastric residence time may
become insufficient due to lowering in the mechanical strength
of the gastric resident layer when the proportion of the
water-soluble ingredient in the gastric resident layer exceeds
50% by weight. For this reason, the proportion of the enteric
ingredient in the gastric resident layer is preferably not less
than 50% by weight, more preferably, not less than 60% by weight
and, still more preferably, not less than 70% by weight of the
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gastric resident layer.
[0042]
To be more specific, when an enteric ingredient and a
water-soluble ingredient are contained in the gastric resident
layer, the amounts of the enteric ingredient and the
water-soluble ingredient in the gastric resident layer are that,
preferably, the enteric ingredient is 50% by weight or more
and the water-soluble ingredient is 50% by weight or less; more
preferably, the enteric ingredient is 60 to 90% by weight and
the water-soluble ingredient is 10 to 40% -by weight; and, still
more preferably, the enteric ingredient is 70 to 85% by weight
and the water-soluble ingredient is 15 to 30% by weight of the
gastric resident layer.
[0043]
When the gastric resident layer containing the acidic
functional group-containing polymer ingredient and the
hydrophobic ingredient additionally contains the
water-soluble ingredient, the gastric residence time may
become insufficient due to lowering in the mechanical strength
when the proportion of the water-soluble ingredient in the
gastric resident layer exceeds 60% by weight. For this reason,
it is preferable that the upper limit of the proportion of the
water-soluble ingredient in the gastric resident layer be 60%
by weight or less and, particularly, 50% by weight or less.
On the other hand, the ease of disintegration in the intestinal
tract may suffer when the proportion of the water-soluble
ingredient in the gastric resident layer is below 5% by weight.
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It is therefore preferable that the lower limit of the
proportion of the water-soluble ingredient in the gastric
resident layer be 5% by weight or more and, particularly, 10%
by weight or more of the gastric resident layer.
[0044]
The gastric resident layer may additionally include an
excipient, a binder, a fluidizer, a lubricant or the like.
Examples of an excipient include microcrystalline cellulose,
corn starch and anhydrous calcium hydrogen phosphate.
Examples of a binder include methyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, povidone,
polyvinyl alcohol, pullulan, polyethylene glycol, gelatin,
gum arabic, pregelatinized starch and partially
pregelatinized starch. Examples of a fluidizer include light
anhydrous silicic acid and hydrate silicon dioxide. Examples
of a lubricant include magnesium stearate, calcium stearate,
polyoxyl stearate, talc, sucrose fatty acid ester, dimethyl
polysiloxane and sodium stearyl fumarate. The proportion of
the ingredient above in the gastric resident layer may be
appropriately decided according to the type and amount of the
other ingredients used.
[0045]
The gastric resident layer may be prepared by ordinary
methods. For example, a method may be used in which the
foregoing ingredients are mixed together and the admixture is
compressed to form the layer under a pressure of 3 kN to 20
kN and, preferably, 5 kN to 15 kN.
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[0046]
A drug releasing layer may be designed, if necessary,
to have an immediate-release drug releasing function together
with a sustained-release drug releasing layer. For example,
it may be made into a three-layered tablet comprising gastric
resident layer, sustained-release drug releasing layer and
immediate-release drug releasing layer or may be made into a
preparation where a gastric resident layer and a
sustained-release drug releasing layer are coated with an
immediate-release drug releasing layer.
[0047]
As a result of applying such an immediate-release drug
releasing layer to the present preparation, it is now possible
that the concentration of levodopa in blood is able to be made
to reach the effective blood level immediately after the
administration whereby, after the administration, quick
improvement in the symptoms of Parkinson's disease is able to
be achieved. Further, due to the dissolution of the drug from
the sustained-release layer after that, it is possible to keep
the constant blood level for long time.
[0048]
Although levodopa contained in the sustained-release
drug releasing layer and the immediate-release drug releasing
layer may be made into any ratio, it is usual that the ratio
of levodopa in the sustained-release drug releasing layer to
the total weight of levodopa in the preparation is not less
than 50%, preferably not less than 70% and, more preferably,
23
CA 02673485 2009-06-19
not less than 80%.
[0049]
As to the ingredient for the drug releasing layer,
various kinds of ingredients which have been known for persons
skilled in the art may be appropriately selected so as to give
function(s) of immediately releasing property and/or
sustainedly releasing property. Examples of the ingredient
as such include microcrystalline cellulose; alkyl celluloses
such as methyl cellulose or ethyl cellulose; hydroxyalkyl
celluloses such as hydroxypropyl cellulose, low substituted
hydroxypropyl cellulose, hydroxypropylmethyl cellulose (2208,
2906, 2910) or hydroxyethyl cellulose; carboxymethyl
celluloses such as carboxymethyl cellulose, carboxymethyl
cellulose calcium or croscarmellose sodium; gums such as guar
gum, xanthan gum or gellan gum; polyethylene oxides; aminoalkyl
methacrylate copolymers; acrylic acid copolymers;
carboxyvinyl polymers; polyvinylpyrrolidones; polyvinyl
alcohols; macrogols; oils and fats such as carnauba wax or
hydrogenated oil; starches such as corn starch, potato starch,
wheat starch, dextrin, pregelatinized starch, partially
pregelatinized starch, carboxymethyl starch sodium or
pullulan; sugars such as lactose or saccharose; sugar alcohols
such as mannitol, xylitol, sorbitol or maltitol; minerals such
as kaolin, talc, magnesium stearate, titanium oxide,
precipitated calcium carbonate or calcium hydrogen phosphate;
and plasticizers such as triethyl citrate, propylene glycol,
triacetin or medium-chain fatty acid triglyceride. Desired
24
CA 02673485 2009-06-19
sustained release conditions can be set by appropriately
selecting these ingredients. Among these ingredients, it is
preferable to include hydroxyalkyl cellulose or polyethylene
oxide. The ingredient may be used either individually or in
a combination of two or more kinds with any proportions.
[0050]
Solubility of levodopa and carbidopa which will be
mentioned later is high under an acidic condition and is low
under a weakly acidic to basic condition. An acidic ingredient
may be included in the drug releasing layer so that a preferred
level in blood is able to be maintained even when gastric pH
changes before and after the meal. As to the acidic ingredients,
there may be used, for example, inorganic acid; organic acid
such as fumaric acid, maleic acid, malonic acid, oxalic acid,
ascorbic acid, malic acid, citric acid or amino acid; enteric
ingredient; carboxymethyl celluloses; and polymer ingredient
selected from the group consisting of polyacrylic acids and
polysaccharides having carboxyl group or sulfo group. Each
of those ingredients may be used solely or two or more thereof
may be used jointly by mixing in any proportion. Among these,
preferred ones are organic acid, carboxymethyl celluloses and
polymer ingredient selected from the group consisting of
polyacrylic acids and polysaccharides having carboxyl group
or sulfo group. When an acidic ingredient is included, it is
also possible to enhance the stability of levodopa and
carbidopa in the drug releasing layer.
[0051]
CA 02673485 2009-06-19
With regard to enteric ingredients, carboxymethyl
celluloses, polyacrylic acids and polysaccharides having
carboxyl group or sulfo group, there may be used the same
ingredient which is used for a gastric resident layer.
[0052]
In the drug releasing layer, it is preferred that a dopa
decarboxylase inhibitor such as carbidopa or benserazide is
contained therein together with levodopa. As a result thereof,
it is possible that metabolism of levodopa in a peripheral site
is inhibited, transfer of levodopa into the brain is enhanced
and an adverse action by dopamine is reduced.
[0053]
When a catechol-0-methyltransferase (COMT) inhibitor
such as entacapone or tolcapone is contained as a medicament
therein, it is preferred since levodopa is able to be
transferred into the brain more efficiently.
[0054]
The drug releasing layer may further contain a medicament
having an effect of improving the parkinsonism and/or an effect
of reducing the adverse action including, for example,
anti-cholinergic agent such as trihexyphenidyl hydrochloride;
dopamine receptor stimulator such as ergot or non-ergot
alkaloid; MAO-B inhibitor such as selegiline hydrochloride;
nor-epinephrine supplementing agent such as droxidopa; and
dopamine release promoter such as amantadine hydrochloride.
[0055]
Levodopa contained in the drug releasing layer of the
26
CA 02673485 2009-06-19
gastric retentive preparation of the present invention is
administered usually in the range of 20 mg to 2000 mg or,
preferably, in the range of 100 mg to 800 mg per day for an
adult. When at least one member selected from the dopa
decarboxylase inhibitor and the COMT inhibitor is further
contained in the drug releasing layer of the gastric retentive
preparation of the present invention, the compounding ratio
of those drugs may be appropriately selected depending upon
age, sex, body weight and symptom of a patient and upon
combination of the drugs. For example, when carbidopa is
further contained in the drug releasing layer, carbidopa is
administered usually in the range of 2 mg to 500 mg or,
preferably, in the range of 20 mg to 200 mg per day for an adult.
When a COMT inhibitor is further contained in the drug releasing
layer, the COMT inhibitor is administered usually in the range
of 20 mg to 2000 mg or, preferably, in the range of 100 mg to
800 mg per day for an adult.
[0056]
The drug releasing layer may be prepared by an ordinary
method. For example, a method may be used in which the
foregoing ingredient and drug are mixed together and the
admixture is compressed to form the layer under a pressure of
3 kN to 20 kN and, preferably, 5 kN to 15 kN.
[0057]
A gastric retentive preparation according to the present
invention may be prepared by methods commonly used for the
preparation of bilayer or multilayer tablets. For example,
27
CA 02673485 2009-06-19
the gastric retentive preparation may be prepared by a method
in which the ingredients respectively used for the gastric
resident layer and the drug releasing layer are separately
loaded into a tableting machine and are compressed into a
bilayer or multilayer tablet under a pressure of 3 kN to 20
kN or, preferably, 5 kN to 15 kN. The bonding of the gastric
resident layer and the drug releasing layer may be made, for
example, by tablet compression of the gastric resident layer
and the drug releasing layer, or by tablet compression using
a bonding layer between the gastric resident layer and the drug
releasing layer, the bonding layer including a binder such as
hydroxypropyl cellulose.
[0058]
The gastric resident layer including the enteric
ingredient, particularly an acrylic acid copolymer, is
relatively hydrophobic while the drug releasing layer
including hydroxyalkyl cellulose or polyethylene oxide is
relatively hydrophilic. For this reason, desirable bonding
may not be achieved by the simple tablet compression of the
two materials. It is therefore preferable, when bonding is
made, to include the water-soluble ingredient in the gastric
resident layer and thereby improve the strength of bonding.
[0059]
In the gastric retentive preparation of the present
invention, although the proportion of the gastric resident
layer to the drug releasing layer may be in any proportion,
the proportion of the gastric resident layer to the total weight
28
CA 02673485 2009-06-19
of the preparation is usually 5 to 50% by weight, preferably
to 45% by weight and, more preferably, 15 to 40% by eight.
[0060]
The gastric retentive preparation may have any shape so
5 far as it is suited for manufacture, ingestion or the like.
Some of the possible shapes are in len.s, disc, circle, caplet,
ellipse, triangle, quadrangle, pentagon, hexagon, flower and
oval.
[0061]
10 Preferably, the gastric retentive preparation is sized
so that the lower limit of its diameter (short axis in the case
of irregular shape) is greater than 6 mm and, particularly,
7 mm or greater. A sufficient gastric residence time may not
be obtained when the diameter is 6 mm or less. The upper limit
of diameter (long axis in the case of irregular shape) may be
any length provided that it permits ingestion. Generally, the
upper limit of diameter is 30 mm or less.
[0062]
For enhancing the identification, the gastric retentive
preparation may contain a colorant, such as a dye, in the drug
releasing layer and/or the gastric resident layer. Any
colorant may be used so far as it is able to be used as a
pharmaceutical and examples thereof include food dyes such as
Food Yellow 5, Food Red 2 or Food Blue 2; food lake dyes; ferric
oxide; yellow ferric oxide; yellow iron oxide; and black iron
oxide.
EXAMPLES
29
CA 02673485 2009-06-19
[0063]
The following will describe the present invention in more
detail based on Examples. The present invention is not limited
in any ways by the following Examples.
[0064]
(Dissolution test)
According to the paddle method described in the JP
dissolution testing method, a test preparation was placed in
a sinker and was immersed in the JP first fluid (900 mL) , which
was then stirred for 15 hours at 37 C at a paddle speed of 200
rpm. The test preparation was gently taken out and was immersed
in the JP second fluid (900 mL) . After stirring the solution
for 9 hours at 37 C at a paddle speed of 200 rpm, the large
diameter of the gastric resident layer of the preparation was
measured with a caliper. In the case where no remains of the
gastric resident layer were observed, or when the remains of
the gastric resident layer appeared spongy or only a small
portion of the soft material was present, the time from the
start of stirring was recorded as the dissolution time.
[0065]
(Strength test)
A 50 mL volume FalconTM conical tube (30 x 115 mm) for
centrifugation (BlueMax; Becton, Dickinson and Company,
Japan) was charged with one tablet of test preparation, 50 g
of glass beads BZ-4 (AS ONE Corporation) having an outer
diameter of 3.962 mm to 4.699 mm, and 30 mL of the JP first
fluid. The tube was horizontally laid and was rotated at 200
CA 02673485 2009-06-19
rpm at 37 C for 10 hours with the JP first fluid (30 mL) replaced
every 2. 5 hours. Thereafter, the small diameter of the gastric
resident layer of the preparation was measured with a caliper.
The test preparation thus obtained was then placed on a
rheometer (Sun Rheo Meter CR-150; Sun Scientific Co., Ltd.),
with the gastric resident layer on top and the drug releasing
layer at the bottom. A maximum load was measured at a
compression clearance of 1 mm and a measurement range of 10
kg, using a 3.5 cm flat circular compression adapter. Fig.
1 illustrates the apparatus used for the test.
[0066]
(Gastric residence time)
The test preparation was orally administered to groups
of 2 to 3 beagles, 8 to 10 months of age, and the dogs were
x-rayed over a time course to measure gastric residence time.
Specifically, each group of beagles was put in a cage with free
access to water. The dogs were fasted for at least 20 hours,
and were given a mixture of 250 g of solid dog food and 50 g
of chum 30 minutes before administration of the preparation.
Upon confirmation that all the food has been eaten, the test
preparation was administered together with 20 mL of water.
This was followed by administration of 20 w/v% barium sulfate
(10 mL/body), and the dogs were deprived of water until the
end of the test. After administration of the test preparation,
the subjects were x-rayed at one hour intervals, and 20 w/v%
barium sulfate (10 mL/body) was administered as appropriate
during the course of x-ray radiography. Note that, the test
31
CA 02673485 2009-06-19
preparation was embedded with a circular tablet for x-ray
imaging at each center of the drug releasing layer and the
gastric resident layer, which tablet had been prepared from
a mixture of barium sulfate (500 mg) and hydroxypropyl
cellulose (HPC-H fine powder, 500 mg) using an IR-measurement
tableting machine measuring 3 mm in diameter. The gastric
residence time was given by the mean value of the time period
from the administration of the test preparation to the last
observation of the preparation in the stomach by x-ray
radiography. For cases the preparation was observed in the
stomach 16 hours after the administration but was not observed
24 hours after the administration, the gastric residence time
was deemed as 16 hours.
[0067]
Reference Example 1
Furosemide (1250 mg), hydroxypropyl methyl cellulose
2208 (Metolose 90SH 4000SR, 3250 mg) and hydroxypropyl
cellulose (HPC-M fine powder, 500 mg) were mixed together in
a mortar to prepare a composition for the drug releasing layer.
Separately, hydroxypropyl methyl cellulose acetate succinate
(Shin-Etsu AQOAT AS-MF, 800 mg), hydroxypropyl cellulose
(HPC-M fine powder, 200 mg) and yellow ferric oxide (5 mg) were
mixed together in a mortar to prepare a composition for the
gastric resident layer. The composition for the drug
releasing layer and the composition for the gastric resident
layer were loaded into a tableting machine (N-30E, Okada Seiko
Co., Ltd.; hereinafter, the same machine will be used) in this
32
CA 02673485 2009-06-19
order and the compositions were compressed into a tablet at
a punch pressure of about 10 kN, using a circular die and punch
measuring 8 mm in diameter. As a result, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (130 mg) and hydroxypropyl cellulose (20
mg) for the drug releasing layer; and hydroxypropyl methyl
cellulose acetate succinate (80 mg), hydroxypropyl cellulose
(20 mg) and yellow ferric oxide (0.5 mg) for the gastric
resident layer. Note that, when loading the composition for
the drug releasing layer, the tablet for x-ray imaging was
placed at the center of the composition after half of the
composition had been loaded, and the rest of the composition
was loaded thereon to embed the tablet for x-ray imaging into
the drug releasing layer. In the same manner, when loading
the composition for the gastric resident layer, the tablet for
x-ray imaging was placed at the center of the composition after
half of the composition had been loaded, and the rest of the
composition was loaded thereon to embed the tablet for x-ray
imaging in the gastric resident layer.
[0068]
(Dissolution test)
Small diameter (JP first fluid): 8.53 mm
Dissolution time (JP second fluid): 3.0 hours
(Strength test)
Small diameter (JP first fluid) : 8.32 mm, maximum load: > 10000
g
33
CA 02673485 2009-06-19
(Confirmation test for gastric residence time)
Gastric residence time: 16 hours
[0069]
Reference Example 2
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (70 mg) ,
lactose (30 mg) and yellow ferric oxide (0.5 mg) for the gastric
resident layer.
[0070]
(Dissolution test)
Small diameter (JP first fluid): 8.42 mm
Dissolution time (JP second fluid): 1.0 hour
(Strength test)
Small diameter (JP first fluid) : 8.23 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 16 hours
[0071]
Reference Example 3
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
34
CA 02673485 2009-06-19
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (Eudragit
L100-55, 80 mg), hydroxypropyl cellulose (20 mg) and yellow
ferric oxide (0.5 mg) for the gastric resident layer.
[0072]
(Dissolution test)
Small diameter (JP first fluid): 9.32 mm
Dissolution time (JP second fluid): 3.0 hours
(Strength test)
Small diameter (JP first fluid) : 9.23 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 16 hours
[0073]
Reference Example 4
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (80 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 20
mg) for the gastric resident layer.
[0074]
(Dissolution test)
Small diameter (JP first fluid): 9.84 mm
Dissolution time (JP second fluid): 5.0 hours
CA 02673485 2009-06-19
(Strength test)
Small diameter (JP first fluid) : 9.31 mm, maximum load: > 10000
g
[0075]
Reference Example 5
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (80 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 4000SR, 20
mg) for the gastric resident layer.
[0076]
(Dissolution test)
Small diameter (JP first fluid): 10.29 mm
Large diameter (JP second fluid): 1.71 mm
(Strength test)
Small diameter (JP first fluid) : 9.41 mm, maximum load: > 10000
g
[0077]
Reference Example 6
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
36
CA 02673485 2009-06-19
and methacrylic acid-ethyl acrylate copolymer (80 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100000SR,
20 mg) for the gastric resident layer.
[0078]
(Strength test)
Small diameter (JP first fluid) : 9. 65 mm, maximum load: > 10000
g
[0079]
Reference Example 7
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (70 mg),
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 4000SR, 20
mg) and lactose (10 mg) for the gastric resident layer.
[0080]
(Dissolution test)
Small diameter (JP first fluid): 10.25 mm
Dissolution time (JP second fluid): 7.0 hours
(Strength test)
Small diameter (JP first fluid): 9.62 mm, maximum load: 9760
g
(Confirmation test for gastric residence time)
Gastric residence time: 19 hours
[0081]
37
CA 02673485 2009-06-19
Reference Example 8
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (60 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 4000SR, 40
mg) for the gastric resident layer.
[0082]
(Strength test)
Small diameter (JP first fluid): 9.34 mm, maximum load: 6490
g
[00831
Reference Example 9
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (70 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 4000SR, 30
mg) for the gastric resident layer.
[0084]
(Dissolution test)
Small diameter (JP first fluid): 10.43 mm
Large diameter (JP second fluid): 1.82 mm
38
CA 02673485 2009-06-19
(Strength test)
Small diameter (JP first fluid) : 9. 90 mm, maximum load: > 10000
g
[0085]
Reference Example 10
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (40 mg) and
hydroxypropyl cellulose (10mg)for the gastric resident layer.
[0086]
(Dissolution test)
Small diameter (JP first fluid): 8.74 mm
Dissolution time (JP second fluid): 3.5 hours
(Strength test)
Small diameter (JP first fluid) : 8.79 mm, maximum load: 6130
g
[0087]
Reference Example 11
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: ciprofloxacin (30 mg),
polyethylene oxide (Polyox WSR-303, 85 mg) and hydroxypropyl
cellulose (85 mg) for the drug releasing layer; and methacrylic
acid-ethyl acrylate copolymer (35 mg) and hydroxypropyl methyl
39
CA 02673485 2009-06-19
cellulose 2208 (Metolose 90SH 100SR, 10 mg) and low substituted
hydroxypropyl cellulose (5 mg) for the gastric resident layer.
[0088]
(Dissolution test)
Small diameter (JP first fluid): 9.65 mm
Dissolution time (JP second fluid): 3.0 hours
(Strength test)
Small diameter (JP first fluid): 9.21 mm, maximum load: 5140
g
(Confirmation test for gastric residence time)
Gastric residence time: 15 hours
[0089]
Reference Example 12
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (Lubriwax 101, hereinafter the same name
will be used; 75 mg) , carboxyvinyl polymer (5 mg) , polyethylene
oxide (Polyox WSR Coagulant; 5 mg) and anhydrous calcium
hydrogen phosphate (15 mg) for the gastric resident layer.
[0090]
(Dissolution test)
Small diameter (JP first fluid): 8.00 mm
Dissolution time (JP second fluid): 8.0 hours
(Strength test)
CA 02673485 2009-06-19
Small diameter (JP first fluid) : 7.00 mm, maximum load: 6720
g
(Confirmation test for gastric residence time)
Gastric residence time: 19 hours
[0091]
Reference Example 13
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and ethyl cellulose (Ethocel STD 10FP, 80 mg), carboxyvinyl
polymer (10 mg) and polyethylene oxide (Polyox WSR 301, 10 mg)
for the gastric resident layer.
[0092]
(Dissolution test)
Small diameter (JP first fluid): 8.82 mm
Large diameter (JP second fluid): 4.14 mm
(Strength test)
Small diameter (JP first fluid): 8.47 mm, maximum load: 7750
g
(Confirmation test for gastric residence time)
Gastric residence time: 16 hours
[0093]
Reference Example 14
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 14
41
CA 02673485 2009-06-19
mm and a small diameter of 7 mm, irregular-shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
furosemide (50 mg), hydroxypropyl methyl cellulose 2208
(Metolose 90SH4000SR, 150mg), hydroxypropyl methyl cellulose
2910 (Metolose 60SH 50, 115 mg) and hydroxypropyl cellulose
(35 mg) for the drug releasing layer; and hydrogenated oil (135
mg), carboxyvinyl polymer (7.5 mg) and crospovidone
(Polyplasdone XL-10, 7.5 mg) for the gastric resident layer.
[0094]
(Dissolution test)
Small diameter (JP first fluid): 7.14 mm
Dissolution time (JP second fluid): 8 hours
(Strength test)
Small diameter (JP first fluid) : 7.05 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 19 hours
[0095]
Reference Example 15
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: furosemide (50 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 150 mg), hydroxypropyl
42
CA 02673485 2009-06-19
methyl cellulose 2910 (Metolose 60SH 50, 205 mg) and
hydroxypropyl cellulose (45 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (140 mg),
hydroxypropyl cellulose (40 mg) and lactose (20 mg) for the
gastric resident layer.
[0096]
(Dissolution test)
Small diameter (JP first fluid): 8.25 mm
Dissolution time (JP second fluid): 7 hours
(Strength test)
Small diameter (JP first fluid) : 7.82 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 16 hours
[0097]
Reference Example 16
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameterof 17.5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: furosemide (50 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 150 mg) , hydroxypropyl
methyl cellulose 2910 (Metolose 60SH 50, 205 mg) and
hydroxypropyl cellulose (45 mg) for the drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (160 mg),
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 40
43
CA 02673485 2009-06-19
mg) for the gastric resident layer.
[0098]
(Dissolution test)
Small diameter (JP first fluid): 8.98 mm
Dissolution time (JP second fluid): 4 hours
(Strength test)
Small diameter (JP first fluid) : 8.55 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 19 hours
[0099]
Reference Example 17
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: furosemide (50 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 150 mg), hydroxypropyl
methyl cellulose 2910 (Metolose 60SH 50, 205 mg) and
hydroxypropyl cellulose (45 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (160 mg)
and hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR,
40 mg) for the gastric resident layer.
[0100]
(Dissolution test)
Small diameter (JP first fluid): 8.76 mm
44
CA 02673485 2009-06-19
Dissolution time (JP second fluid): 4 hours
(Strength test)
Small diameter (JP first fluid) : 8.43 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 17 hours
[0101]
Reference Example 18
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 14
mm and a small diameter of 7 mm, irregular-shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
furosemide (50 mg), hydroxypropyl methyl cellulose 2208
(Metolose 90SH4000SR, 150 mg), hydroxypropyl methyl cellulose
2910 (Metolose 60SH 50, 115 mg) and hydroxypropyl cellulose
(35 mg) for the drug releasing layer; and methacrylic
acid-ethyl acrylate copolymer (52.5 mg), hydroxypropyl methyl
cellulose acetate succinate (52.5 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 100SR, 30 mg) and lactose (15
mg) for the gastric resident layer.
[0102]
(Dissolution test)
Small diameter (JP first fluid): 8.79 mm
Dissolution time (JP second fluid): 5 hours
(Strength test)
Small diameter (JP first fluid): 8.35 mm, maximum load: 7940
CA 02673485 2009-06-19
g
(Confirmation test for gastric residence time)
Gastric residence time: 18 hours
[0103]
Reference Example 19
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: furosemide (50 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 150 mg), hydroxypropyl
methyl cellulose 2910 (Metolose 60SH 50, 205 mg) and
hydroxypropyl cellulose (45 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (160 mg)
and hydroxypropyl cellulose (40 mg) for the gastric resident
layer.
[0104]
(Dissolution test)
Small diameter (JP first fluid): 8.21 mm
Dissolution time (JP second fluid): 4 hours
(Strength test)
Small diameter (JP fir.st fluid) : 7.97 mm, maximum load: > 10000
g
[0105]
Reference Example 20
According to Reference Example 1, flat circular tablets
46
CA 02673485 2009-06-19
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (100 mg)
for the gastric resident layer.
[0106]
(Dissolution test)
Small diameter (JP first fluid): 8.09 mm
Dissolution time (JP second fluid): 2.5 hours
(Strength test)
Small diameter (JP first fluid) : 8. 00 mm, maximum load: > 10000
g
[0107]
Reference Example 21
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (70 mg)
and hydroxypropyl cellulose (30 mg) for the gastric resident
layer.
[0108]
(Dissolution test)
Small diameter (JP first fluid): 9.00 mm
Dissolution time (JP second fluid): 8 hours
47
CA 02673485 2009-06-19
(Strength test)
Small diameter (JP first fluid) : 8.51 mm, maximum load: 6770
g
[0109]
Reference Example 22
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (60 mg),
hydroxypropyl cellulose (5 mg) and lactose (35 mg) for the
gastric resident layer.
[0110]
(Dissolution test)
Small diameter (JP first fluid): 8.38 mm
Dissolution time (JP second fluid): 2 hours
(Strength test)
Small diameter (JP first fluid): 8.20 mm, maximum load: 8460
g
[0111]
Reference Example 23
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
48
CA 02673485 2009-06-19
and methacrylic acid-ethyl acrylate copolymer (40 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 10
mg) for the gastric resident layer.
[0112]
(Dissolution test)
Small diameter (JP first fluid): 9.34 mm
Dissolution time (JP second fluid): 2 hours
(Strength test)
Small diameter (JP first fluid): 9.35 mm, maximum load: 6790
g
[0113]
Reference Example 24
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: ciprofloxacin (30 mg),
polyethylene oxide (Polyox WSR-303, 85 mg) and hydroxypropyl
cellulose (85mg) for the drug releasing layer; and methacrylic
acid-ethyl acrylate copolymer (35 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 100SR, 10 mg) and carmellose
calcium (5 mg) for the gastric resident layer.
[0114]
(Dissolution test)
Small diameter (JP first fluid): 9.59 mm
Dissolution time (JP second fluid): 3 hours
(Strength test)
Small diameter (JP first fluid): 8.96 mm, maximum load: 5120
g
49
CA 02673485 2009-06-19
[0115]
Reference Example 25
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and milled hydroxypropyl methyl cellulose phthalate 200731
(HPMCPHP-55, 80 mg) and hydroxypropyl cellulose (20 mg) for
the gastric resident layer.
[0116]
(Dissolution test)
Small diameter (JP first fluid): 8.34 mm
Dissolution time (JP second fluid): 5 hours
(Strength test)
Small diameter (JP first fluid) : 8.14 mm, maximum load: > 10000
g
[0117]
Reference Example 26
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and milled cellulose acetate phthalate (80 mg) and
hydroxypropyl cellulose (20mg)for the gastric resident layer.
[0118]
CA 02673485 2009-06-19
(Dissolution test)
Small diameter (JP first fluid): 8.31 mm
Dissolution time (JP second fluid): 2.5 hours
(Strength test)
Small diameter (JP first fluid) : 7.82 mm, maximum load: > 10000
g
[0119]
Reference Example 27
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: ciprofloxacin (30 mg),
polyethylene oxide (Polyox WSR-303, 85 mg) and hydroxypropyl
cellulose (85 mg) for the drug releasing layer; and
hydrogenated oil (90mg), polyethylene oxide (Polyox WSR N-750,
5 mg) and carmellose calcium (ECG-505, 5 mg) for the gastric
resident layer.
[0120]
(Dissolution test)
Small diameter (JP first fluid): 8.03 mm
Long diameter (JP second fluid): 5.34 mm
(Strength test)
Small diameter (JP first fluid) : 8.12 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 14 hours
[0121]
Reference Example 28
51
CA 02673485 2009-06-19
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: metformin (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 30000F, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (80 mg) , carboxyvinyl polymer (10 mg) and
polyethylene oxide (Polyox WSR 301, 10 mg) for the gastric
resident layer.
[0122]
(Dissolution test)
Small diameter (JP first fluid): 9.00 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid): 8.80 mm, maximum load: 5160
g
[0123]
Reference Example 29
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (70 mg), carboxyvinyl polymer (5 mg),
polyethylene oxide (Polyox WSR coagulant, 5 mg) and anhydrous
calcium hydrogen phosphate (20 mg) for the gastric resident
layer.
[0124]
52
CA 02673485 2009-06-19
(Dissolution test)
Small diameter (JP first fluid): 8.27 mm
Large diameter (JP second fluid): 4.85 mm
(Strength test)
Small diameter (JP first fluid) : 7.70 mm, maximum load: 5300
g
[0125]
Reference Example 30
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (75 mg), carboxyvinyl polymer (10 mg),
polyethylene oxide (Polyox WSR coagulant, 10 mg) and
microcrystalline cellulose (Avicel PH 101, 5 mg) for the
gastric resident layer.
[0126]
(Dissolution test)
Small diameter (JP first fluid): 9.21 mm
Large diameter (JP second fluid): 5.79 mm
(Strength test)
Small diameter (JP first fluid): 8.70 mm, maximum load: 5180
g
[0127]
Reference Example 31
According to Reference Example 1, flat circular tablets
53
CA 02673485 2009-06-19
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (80 mg), carboxyvinyl polymer (5 mg),
polyethylene oxide (Polyox WSR Coagulant, 5 mg) and anhydrous
calcium hydrogen phosphate (10 mg) for the gastric resident
layer.
[0128]
(Dissolution test)
Small diameter (JP first fluid): 8.27 mm
Large diameter (JP second fluid): 4.84 mm
(Strength test)
Small diameter (JP first fluid): 8.01 mm, maximum load: 8090
g
[0129]
Reference Example 32
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (90 mg) , carboxyvinyl polymer (5 mg) and
polyethylene oxide (Polyox WSR -N750, 5 mg) for the gastric
resident layer.
[0130]
(Dissolution test)
54
CA 02673485 2009-06-19
Small diameter (JP first fluid): 9.21 mm
Large diameter (JP second fluid): 4.13 mm
(Strength test)
Small diameter (JP first fluid) : 8. 10 mm, maximum load: > 10000
g
[0131]
Reference Example 33
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (90 mg) and carboxyvinyl polymer (10 mg)
for the gastric resident layer.
[0132]
(Dissolution test)
Small diameter (JP first fluid): 8.41 mm
Large diameter (JP second fluid): 4.77 mm
(Strength test)
Small diameter (JP first fluid) : 8.26 mm, maximum load: > 10000
g
[0133]
Reference Example 34
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
CA 02673485 2009-06-19
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (90 mg), polyethylene oxide (Polyox
WSR-N750, 5 mg) and sodium carboxymethyl starch (Primogel, 5
mg) for the gastric resident layer.
[0134]
(Dissolution test)
Small diameter (JP first fluid): 8.08 mm
Large diameter (JP second fluid): 5.53 mm
(Strength test)
Sma11 diameter (JP first fluid) : 8.02 mm, maximum load: > 10000
g
[0135]
Reference Example 35
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydrogenated oil (90 mg) , carboxyvinyl polymer (5 mg) and
povidone (Plasdone K 29/32, 5 mg) for the gastric resident
layer.
[0136]
(Dissolution test)
Small diameter (JP first fluid): 8.00 mm
Large diameter (JP second fluid): 4.97 mm
(Strength test)
Small diameter (JP first fluid) : 8. 05 mm, maximum load: > 10000
56
CA 02673485 2009-06-19
g
[0137]
Reference Example 36
According to Reference Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: furosemide (50 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 150 mg), hydroxypropyl
methyl cellulose 2910 (Metolose 60SH 50, 205 mg) and
hydroxypropyl cellulose (45 mg) for the drug releasing layer;
and xanthan gum (180 mg), hydroxypropyl methyl cellulose 2208
(Metolose 90SH 30000F, 157.5 mg), microcrystalline cellulose
(76.5 mg) and guar gum (36 mg) for the gastric resident layer.
[0138]
(Dissolution test)
Small diameter (JP first fluid): 9.30 mm
Large diameter (JP second fluid): 21.74 mm
(Strength test)
Small diameter (JP first fluid): 7.59 mm, maximum load: 4520
g
(Confirmation test for gastric residence time)
Gastric residence time: 8 hours
[0139]
Separately, the preparation was orally administered to
beagles. The abdomen was opened 8 hours after the
57
CA 02673485 2009-06-19
administration and the preparation remaining in the stomach
was taken out to measure the small diameter of the gastric
resident layer and maximum load of the preparation (in vivo
strength test) Note that, the preparation was also treated
in JP first fluid at 37 C for 8 hours to measure the small
diameter and maximum load of the gastric resident layer
according to the strength test described above (in vitro
strength test).
[0140]
(in vivo strength test)
Small diameter: 7.18 mm; maximum load: 6370 g
(in vitro strength test)
Small diameter: 8.49 mm; maximum load: 6460 g
[0141]
From the result that the values of the in vivo strength
test well coincide with the values of the in vitro strength
test, it can be said that the in vitro strength test reflects
the erosion of the preparation in the stomach.
[0142]
Reference Example 37
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and ethyl cellulose (Ethocel STD 10 FP, 50 mg), hydrogenated
oil (50 mg) and yellow ferric oxide (0.5 mg) for the gastric
58
CA 02673485 2009-06-19
resident layer.
[0143]
(Dissolution test)
Small diameter (JP first fluid): 8.00 mm
Large diameter (JP second fluid): 8.00 mm
(Strength test)
Small diameter (JP first fluid) : 8.00 mm, maximum load: > 10000
g
(Confirmation test for gastric residence time)
Gastric residence time: 20 hours
[0144]
Reference Example 38
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and hydroxypropyl methyl cellulose 2208 (Metolose 90SH
100000SR, 100 mg) and yellow ferric oxide (0.5 mg) for the
gastric resident layer.
[0145]
(Dissolution test)
Small diameter (JP first fluid): 9.45 mm
Large diameter (JP second fluid): 7.02 mm
(Strength test)
Small diameter (JP first fluid): 7.15 mm, maximum load: 2570
g
59
CA 02673485 2009-06-19
(Confirmation test for gastric residence time)
Gastric residence time: 8 hours
[0146]
Reference Example 39
According to Reference Example 1, flat circular tablets
of gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: furosemide (50 mg), hydroxypropyl
methyl cellulose 2208 (Metolose 90SH 4000SR, 130 mg) and
hydroxypropyl cellulose (20 mg) for the drug releasing layer;
and carboxyvinyl polymer (Carbopol 971P, 50 mg), polyethylene
oxide (Polyox Coagulant, 50 mg) and yellow ferric oxide (0.5
mg) for the gastric resident layer.
[0147]
(Dissolution test)
Small diameter (JP first fluid): 10.68 mm
Large diameter (JP second fluid): 19.28 mm
(Strength test)
Small diameter (JP first fluid) : 10. 67 mm, maximum load: 2910
g
(Confirmation test for gastric residence time)
Gastric residence time: 10 hours
[0148]
Reference Example 40
According to Reference Example 1 except for using a flat
circular die and punch having a diameter of 6 mm, fiat circular
tablets of gastric retentive preparation having a diameter of
6 mm were prepared, each containing: furosemide (50 mg),
CA 02673485 2009-06-19
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100000SR,
40 mg) and hydroxypropyl cellulose (10 mg) for the drug
releasing layer; and ethyl cellulose (Ethocel STD 10FP, 12.5
mg), hydrogenated oil (12.5 mg), barium sulfate (25 mg) and
yellow ferric oxide (0.5 mg) for the gastric resident layer.
[0149]
(Dissolution test)
Small diameter (JP first fluid): 6.00 mm
Large diameter (JP second fluid): 6.00 mm
(Strength test)
Small diameter (JP first fluid): 6.00 mm, maximum load: 2020
g
(Confirmation test for gastric residence time)
Gastric residence time: 6 hours
[0150]
Example 1
Levodopa (3100 mg), carbidopa (775 mg), hydroxypropyl
methyl cellulose 2208 (Methocel K100M P CR, 1356.25 mg) and
microcrystalline cellulose (Ceolus PH101, 193.75 mg) were
mixed in a mortar to prepare a composition for a drug releasing
layer. Separately, methacrylic acid-ethyl acrylate copolymer
(Eudragit L100-55, 1860 mg) and hydroxypropyl methyl cellulose
2208 (Metolose 90SH 100SR, 465 mg) were mixed in a mortar to
prepare a composition for a gastric resident layer. Firstly,
the composition for a drug releasing layer was charged in a
tableting machine and then the composition for a gastric
resident layer was charged therein and subjected to a
61
CA 02673485 2009-06-19
compressive molding with a tableting pressure of about 10 kN
using an irregularly shaped die and punch where a large diameter
was 14 mm and a small diameter was 7 mm to prepare a gastric
retentive preparation in an irregularly shaped tablets of 14
mm large diameter and 7 mm small diameter containing: levodopa
(200 mg), carbidopa (50 mg), hydroxypropyl methyl cellulose
2208 (87.5 mg) and microcrystalline cellulose (12.5 mg) in a
drug releasing layer; and methacrylic acid-ethyl acrylate
copolymer (120 mg) and hydroxypropyl methyl cellulose 2208 (30
mg) in a gastric resident layer per tablet.
[0151]
Example 2
According to Example 1, irregularly shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg), carbidopa (50 mg), hydroxypropyl methyl
cellulose 2208 (Methocel K100M P CR, 50 mg) and
microcrystalline cellulose (50 mg) for the drug releasing
layer; and methacrylic acid-ethyl acrylate copolymer (120 mg)
and hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR,
mg) for the gastric resident layer.
[0152]
Example 3
According to Example 1, irregularly shaped tablets of
25 gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg), carbidopa (50 mg), hydroxypropyl methyl
62
CA 02673485 2009-06-19
cellulose 2208 (Methocel K100M P CR, 75 mg) and
microcrystalline cellulose (25 mg) for the drug releasing
layer; and methacrylic acid-ethyl acrylate copolymer (120 mg)
and hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR,
30 mg) for the gastric resident layer.
[0153]
Example 4
According to Example 1, irregularly shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg) , carbidopa (50 mg) and hydroxypropyl methyl
cellulose 2208 (Methocel K100M P CR, 100 mg) for the drug
releasing layer; and methacrylic acid-ethyl acrylate
copolymer (120 mg) and hydroxypropyl methyl cellulose 2208
(Metolose 90SH 100SR, 30 mg) for the gastric resident layer.
[0154]
(Dissolution test)
Small diameter (JP first fluid): 8.56 mm
Dissolution time (JP second fluid): 6 hours
(Strength test)
Small diameter (JP first fluid) : 8.34 mm, maximum load: > 10000
g
[0155]
Example 5
According to Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
63
CA 02673485 2009-06-19
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: levodopa (200 mg), carbidopa (50 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 75
mg) and microcrystalline cellulose (125 mg) for the drug
releasing layer; and methacrylic acid-ethyl acrylate
copolymer (160 mg) and hydroxypropyl methyl cellulose 2208
(Metolose 90SH 100SR, 40 mg) for the gastric resident layer.
[0156]
Example 6
According to Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: levodopa (200 mg), carbidopa (50 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 100
mg) and microcrystalline cellulose (100 mg) for the drug
releasing layer; and methacrylic acid-ethyl acrylate
copolymer (160 mg) and hydroxypropyl methyl cellulose 2208
(Metolose 90SH 100SR, 40 mg) for the gastric resident layer.
[0157]
(Dissolution test)
Small diameter (JP first fluid): 9.46 mm
Dissolution time (JP second fluid): 5.8 hours
(Strength test)
Small diameter (JP first fluid) : 8.89 mm, maximum load: > 10000
64
CA 02673485 2009-06-19
g
[0158]
Example 7
According to Example 1, irregularly shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg) , carboxyvinyl polymer (Carbopol 971P, 20 mg) ,
anhydrous calcium hydrogen phosphate (20 mg) and hydroxypropyl
methyl cellulose 2208 (Methocel K100M P CR, 150 mg) for the
drug releasing layer; and methacrylic acid-ethyl acrylate
copolymer (120 mg) and hydroxypropyl cellulose (HPC-M fine
powder, 30 mg) for the gastric resident layer.
[0159]
(Dissolution test)
Small diameter (JP first fluid): 8.14 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid) : 8. 16 mm, maximum load: > 10000
g
[0160]
Example 8
Levodopa (2550 mg) , carbidopa (255 mg) , corn starch (255
mg) and povidone (Plasdone K29/32, 102 mg) were mixed in a
mortar and water was added thereto to granulate. The granules
were dried at 60 C and sieved to prepare granules of
levodopa-carbidopa. To the levodopa-carbidopa granules (1922
mg) were added hydroxypropyl methyl cellulose 2208 (Methocel
CA 02673485 2009-06-19
K100MP CR, 496 mg) and carboxyvinyl polymer (Carbopol 971P,
124 mg) followed by mixing in a glass bottle to prepare a
composition for a drug releasing layer. Separately,
methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55,
1860 mg) and hydroxypropyl cellulose (HPC-M fine powder, 465
mg) were mixed in a mortar to prepare a composition for a gastric
resident layer. Firstly, the composition for a drug releasing
layer was charged in a tableting machine and then the
composition for a gastric resident layer was charged therein
and the mixture was subjected to a compressive molding with
a tableting pressure of about 10 kN using an irregularly shaped
die and punch where a large diameter was 14 mm and a small
diameter was 7 mm to prepare a gastric retentive preparation
in an irregularly shaped tablets of 14 mm large diameter and
7 mm small diameter containing: levodopa (250 mg), carbidopa
(25 mg) , corn starch (25 mg) , povidone (10 mg) , hydroxypropyl
methyl cellulose 2208 (80 mg) and carboxyvinyl polymer (20 mg)
for a drug releasing layer; and methacrylic acid-ethyl acrylate
copolymer (120 mg) and hydroxypropyl cellulose (30 mg) for a
gastric resident layer per tablet.
[0161]
Example 9
Levodopa (2040 mg) , carbidopa (510mg),microcrystalline
cellulose (Ceolus PH101, 102 mg), methacrylic acid-ethyl
acrylate copolymer (Eudragit L100-55, 102 mg) and povidone
(Plasdone K29/32, 102 mg) were mixed in a mortar and 99.5%
ethanol was added thereto to granulate. The granules were
66
CA 02673485 2009-06-19
dried at 60 C and sieved to prepare granules of
levodopa-carbidopa. To the levodopa-carbidopa granules (1736
mg) was added hydroxypropyl methyl cellulose 2208 (Methocel
K100MP CR, 620 mg) followed by mixing in a glass bottle to
prepare a composition for a drug releasing layer. Separately,
methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55,
1860 mg) and hydroxypropyl cellulose (HPC-M fine powder, 465
mg) were mixed in a mortar to prepare a composition for a gastric
resident layer. Firstly, the composition for a drug releasing
layer was charged in a tableting machine and then the
composition for a gastric resident layer was charged therein
and the mixture was subjected to a compressive molding with
a tableting pressure of about 10 kN using an irregularly shaped
die and punch where a large diameter was 14 mm and a small
diameter was 7 mm to prepare a gastric retentive preparation
in an irregularly shaped tablets of 14 mm large diameter and
7 mm small diameter containing: levodopa (200 mg), carbidopa
(50 mg), microcrystalline cellulose (10 mg), methacrylic
acid-ethyl acrylate copolymer (10 mg), povidone (10 mg) and
hydroxypropyl methyl cellulose 2208 (100 mg) for a drug
releasing layer; and methacrylic acid-ethyl acrylate
copolymer (120 mg) and hydroxypropyl cellulose (30 mg) for a
gastric resident layer per tablet.
[0162]
Example 10
Levodopa (2040 mg) , carbidopa (510mg), microcrystalline
cellulose (Ceolus PH101, 102 mg), hydroxypropyl methyl
67
CA 02673485 2009-06-19
cellulose acetate succinate (HPMCAS-MF, 102mg) and povidone
(Plasdone K29/32, 102 mg) were mixed in a mortar and 99.5%
ethanol was added thereto to granulate. The granules were
dried at 60 C and sieved to prepare granules of
levodopa-carbidopa. To the levodopa-carbidopa granules (1736
mg) was added hydroxypropyl methyl cellulose 2208 (Methocel
K100MP CR, 620 mg) followed by mixing in a glass bottle to
prepare a composition for a drug releasing layer. Separately,
hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF,
1627.5 mg) and lactose (697.5 mg) were mixed in a mortar to
prepare a composition for a gastric resident layer. Firstly,
the composition for a drug releasing layer was charged in a
tableting machine and then the composition for a gastric
resident layer was charged therein and the mixture was
subjected to a compressive molding with a tableting pressure
of about 10 kN using an irregularly shaped die and punch where
a large diameter was 14 mm and a small diameter was 7 mm to
prepare a gastric retentive preparation in an irregularly
shaped tablets of 14 mm large diameter and 7 mm small diameter
containing: levodopa (200 mg), carbidopa (50 mg),
microcrystalline cellulose (10 mg), hydroxypropyl methyl
cellulose acetate succinate (10 mg), povidone (10 mg) and
hydroxypropyl methyl cellulose 2208 (100 mg) for a drug
releasing layer; and hydroxypropyl methyl cellulose acetate
succinate (105 mg) and lactose (45 mg) for a gastric resident
layer per tablet.
[0163]
68
CA 02673485 2009-06-19
Example 11
Levodopa (2040 mg) , carbidopa (510mg), microcrystalline
cellulose (Ceolus PH101, 102 mg), xanthan gum (102 mg) and
povidone(Plasdone K29/32, 102 mg) were mixed in a mortar and
water was added thereto to granulate. The granules were dried
at 60 C and sieved to prepare granules of levodopa-carbidopa.
To the levodopa-carbidopa granules (1736 mg) was added
hydroxypropyl methyl cellulose 2208 (Methocel K100MP CR, 620
mg) followed by mixing in a glass bottle to prepare a
composition for a drug releasing layer. Separately,
hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF,
1627.5 mg) and lactose (697.5 mg) were mixed in a mortar to
prepare a composition for a gastric resident layer. Firstly,
the composition for a drug releasing layer was charged in a
tableting machine and then the composition for a gastric
resident layer was charged therein and the mixture was
subjected to a compressive molding with a tableting pressure
of about 10 kN using an irregularly shaped die and punch where
a large diameter was 14 mm and a small diameter was 7 mm to
prepare a gastric retentive preparation in an irregularly
shaped tablets of 14 mm large diameter and 7 mm small diameter
containing: levodopa (200 mg), carbidopa (50 mg),
microcrystalline cellulose (10 mg), xanthan gum (10 mg),
povidone (10 mg) and hydroxypropyl methyl cellulose 2208 (100
mg) for a drug releasing layer; and hydroxypropyl methyl
cellulose acetate succinate (105 mg) and lactose (45 mg) for
a gastric resident layer per tablet.
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CA 02673485 2009-06-19
[0164]
Example 12
Levodopa (2040mg), carbidopa (510mg), microcrystalline
cellulose (Ceolus PH101, 102 mg), gellan gum (102 mg) and
povidone (Plasdone K29/32, 102 mg) were mixed in a mortar and
water was added thereto to granulate. The granules were dried
at 60 C and sieved to prepare granules of levodopa-carbidopa.
To the levodopa-carbidopa granules (1736 mg) was added
hydroxypropyl methyl cellulose 2208 (Methocel K100MP CR, 620
mg) followed by mixing in a glass bottle to prepare a
composition for a drug releasing layer. Separately,
hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF,
1627.5 mg) and lactose (697.5 mg) were mixed in a mortar to
prepare a composition for a gastric resident layer. Firstly,
the composition for a drug releasing layer was charged in a
tableting machine and then the composition for a gastric
resident layer was charged therein and the mixture was
subjected to a compressive molding with a tableting pressure
of about 10 kN using an irregularly shaped die and punch where
a large diameter was 14 mm and a small diameter was 7 mm to
prepare a gastric retentive preparation in an irregularly
shaped tablets of 14 mm large diameter and 7 mm small diameter
containing: levodopa (200 mg), carbidopa (50 mg),
microcrystalline cellulose (10 mg), gellan gum (10 mg),
povidone (10 mg) and hydroxypropyl methyl cellulose 2208 (100
mg) for a drug releasing layer; and hydroxypropyl methyl
cellulose acetate succinate (105 mg) and lactose (45 mg) for
CA 02673485 2009-06-19
a gastric resident layer per tablet.
[0165]
Example 13
Levodopa (8200 mg), carbidopa (2050 mg),
microcrystalline cellulose (410 mg) and carboxyvinyl polymer
(Carbopol 971P, 410 mg) were mixed in a mortar and water was
added thereto to granulate. The granules were dried at 60 C
and sieved to prepare granules of levodopa-carbidopa. To the
levodopa-carbidopa granules (1674 mg) was added hydroxypropyl
methyl cellulose 2208 (Methocel K100MP CR, 620 mg) followed
by mixing in a glass bottle to prepare a composition for a drug
releasing layer. Separately, methacrylic acid-ethyl acrylate
copolymer (Eudragit L100-55, 1076.25 mg), hydroxypropyl
methyl cellulose acetate succinate (HPMCAS-MF, 1076.25 mg),
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 615
mg) and lactose (307.5 mg) were mixed in a mortar to prepare
a composition for a gastric resident layer. Firstly, the
composition for a drug releasing layer was charged in a
tableting machine and then the composition for a gastric
resident layer was charged therein and the mixture was
subjected to a compressive molding with a tableting pressure
of about 10 kN using an irregularly shaped die and punch where
a large diameter was 14 mm and a small diameter was 7 mm to
prepare a gastric retentive preparation in an irregularly
shaped tablets of 14 mm large diameter and 7 mm small diameter
containing: levodopa (200 mg), carbidopa (50 mg),
microcrystalline cellulose (10 mg), carboxyvinyl polymer (10
71
CA 02673485 2009-06-19
mg) and hydroxypropyl methyl cellulose 2208 (100 mg) for a drug
releasing layer; and methacrylic acid-ethyl acrylate
copolymer (52.5 mg), hydroxypropyl methyl cellulose acetate
succinate (52.5 mg), hydroxypropyl methyl cellulose 2208 (30
mg) and lactose (15 mg) for a gastric resident layer per tablet.
[0166]
(Dissolution test)
Small diameter (JP first fluid): 8.67 mm
Dissolution time (JP second fluid): 4 hours
(Strength test)
Small diameter (JP first fluid): 8.23 mm, maximum load: 7055
g
[0167]
Example 14
According to Example 13, granules of levodopa-carbidopa
were prepared. To the levodopa-carbidopa granules (1674 mg)
was added polyethylene oxide (Polyox WSR 303, 620 mg) followed
by mixing in a glass bottle to prepare a composition for a drug
releasing layer. Separately, methacrylic acid-ethyl acrylate
copolymer (Eudragit L100-55, 2152.5 mg), hydroxypropyl methyl
cellulose 2208 (Metolose 90SH 4000SR, 615 mg) and lactose
(307.5 mg) were mixed in a mortar to prepare a composition for
a gastric resident layer. Firstly, the composition for a drug
releasing layer was charged in a tableting machine and then
the composition for a gastric resident layer was charged
therein and the mixture was subjected to a compressive molding
with a tableting pressure of about 10 kN using an irregularly
72
CA 02673485 2009-06-19
shaped die and punch where a large diameter was 14 mm and a
small diameter was 7 mm to prepare a gastric retentive
preparation in an irregularly shaped tablets of 14 mm large
diameter and 7 mm small diameter containing: levodopa (200 mg) ,
carbidopa (50 mg), microcrystalline cellulose (10 mg),
carboxyvinyl polymer (10 mg) and polyethylene oxide (100 mg)
for a drug releasing layer; and methacrylic acid-ethyl acrylate
copolymer (105 mg), hydroxypropyl methyl cellulose 2208 (30
mg) and lactose (15 mg) for a gastric resident layer per tablet.
[0168]
(Dissolution test)
Small diameter (JP first fluid): 10.29 mm
Dissolution time (JP second fluid): 4.3 hours
(Strength test)
Small diameter (JP first fluid): 9.43 mm, maximum load: 9945
g
[01691
Example 15
According to Example 13, granules of levodopa-carbidopa
were prepared. To the levodopa-carbidopa granules (1674 mg)
was added hydroxypropyl cellulose (HPC-M fine powder, 620 mg)
followed by mixing in a glass bottle to prepare a composition
for a drug releasing layer. Separately, hydrogenated oil
(2767.5 mg), carboxyvinyl polymer (Carbopol 971P, 153.75 mg)
and crospovidone (Polyplasdone XL-10, 153.75 mg) were mixed
in a mortar to prepare a composition for a gastric resident
layer. Firstly, the composition for a drug releasing layer
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CA 02673485 2009-06-19
was charged in a tableting machine and then the composition
for a gastric resident layer was charged therein and the mixture
was subjected to a compressive molding with a tableting
pressure of about 10 kN using an irregularly shaped die and
punch where a large diameter was 14 mm and a small diameter
was 7 mm to prepare a gastric retentive preparation in an
irregularly shaped tablets of 14 mm large diameter and 7 mm
small diameter containing: levodopa (200 mg), carbidopa (50
mg), microcrystalline cellulose (10 mg), carboxyvinyl polymer
(10 mg) and hydroxypropyl cellulose (100 mg) for a drug
releasing layer; and carboxyvinyl polymer (7.5 mg) and
crospovidone (7.5 mg) for a gastric resident layer per tablet.
[0170]
(Dissolution test)
Small diameter (JP first fluid): 7.25 mm
Dissolution time (JP second fluid): 7 hours
(Strength test)
Small diameter (JP first fluid): 7.05 mm, maximum load: 9505
g
[0171]
Example 16
According to Example 13, granules of levodopa-carbidopa
were prepared. To the levodopa-carbidopa granules (1674 mg)
were added hydroxypropyl methyl cellulose 2208 (Methocel
K100MP CR, 496 mg) and carboxyvinyl polymer (Carbopol 971P,
124 mg) followed by mixing in a glass bottle to prepare a
composition for a drug releasing layer. Separately,
74
CA 02673485 2009-06-19
hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF,
2460 mg) and hydroxypropyl cellulose (HPC-M fine powder, 615
mg) were mixed in a mortar to prepare a composition for a gastric
resident layer. Firstly, the composition for a drug releasing
layer was charged in a tableting machine and then the
composition for a gastric resident layer was charged therein
and the mixture was subjected to a compressive molding with
a tableting pressure of about 10 kN using an irregularly shaped
die and punch where a large diameter was 14 mm and a small
diameter was 7 mm to prepare a gastric retentive preparation
in an irregularly shaped tablets of 14 mm large diameter and
7 mm small diameter containing: levodopa (200 mg), carbidopa
(50 mg), microcrystalline cellulose (10 mg), carboxyvinyl
polymer (30 mg) and hydroxypropyl methyl cellulose 2208 (80
mg) for a drug releasing layer; and hydroxypropyl methyl
cellulose acetate succinate (120 mg) and hydroxypropyl
cellulose (30 mg) for a gastric resident layer per tablet.
[0172]
(Dissolution test)
Small diameter (JP first fluid): 7.39 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid): 7.34 mm, maximum load: 9350
g
[0173]
Example 17
According to Example 13, granules of levodopa-carbidopa
CA 02673485 2009-06-19
were prepared. To the levodopa-carbidopa granules (1674 mg)
were added polyethylene oxide (Polyox WSR 303, 310 mg) and
carboxyvinyl polymer (Carbopol 971P, 310 mg) followed by mixing
in a glass bottle to prepare a composition for a drug releasing
layer. Separately, hydrogenated oil (2306.25 mg),
carboxyvinyl polymer (153.75 mg), polyethylene oxide (Polyox
Coagulant, 153.75 mg) and anhydrous calcium hydrogen phosphate
(461.25 mg) were mixed in a mortar to prepare a composition
for a gastric resident layer. Firstly, the composition for
a drug releasing layer was charged in a tableting machine and
then the composition for a gastric resident layer was charged
therein and the mixture was subjected to a compressive molding
with a tableting pressure of about 10 kN using an irregularly
shaped die and punch where a large diameter was 14 mm and a
small diameter was 7 mm to prepare a gastric retentive
preparation in an irregularly shaped tablets of 14 mm large
diameter and 7 mm small diameter containing: levodopa (200 mg) ,
carbidopa (50 mg), microcrystalline cellulose (10 mg),
carboxyvinyl polymer (60 mg) and polyethylene oxide (50 mg)
for a drug releasing layer; and hydrogenated oil (112.5 mg),
carboxyvinyl polymer (7. 5 mg ), polyethylene oxide (7. 5 mg) and
anhydrous calcium hydrogen phosphate (22.5 mg) for a gastric
resident layer per tablet.
[0174]
(Dissolution test)
Small diameter (JP first fluid): 7.13 mm
Dissolution time (JP second fluid): 9 hours
76
CA 02673485 2009-06-19
(Strength test)
Small diameter (JP first fluid) : 7.37 mm, maximum load: 8300
g
[0175]
Example 18
According to Example 13, granules of levodopa-carbidopa
were prepared. To the levodopa-carbidopa granules (1674 mg)
were added hydrogenated oil (496 mg) and lactose (124 mg)
followed by mixing in a glass bottle to prepare a composition
for a drug releasing layer. Separately, ethyl cellulose
(Ethocel STD 10FP, 2460 mg), carboxyvinyl polymer (Carbopol
971P, 307.5 mg) and polyethylene oxide (Polyox WSR 301, 307.5
mg) were mixed in a mortar to prepare a composition for a gastric
resident layer. Firstly, the composition for a drug releasing
layer was charged in a tableting machine and then the
composition for a gastric resident layer was charged therein
and the mixture was subjected to a compressive molding with
a tableting pressure of about 10 kN using an irregularly shaped
die and punch where a large diameter was 14 mm and a small
diameter was 7 mm to prepare a gastric retentive preparation
in an irregularly shaped tablets of 14 mm large diameter and
7 mm small diameter containing: levodopa (200 mg), carbidopa
(50 mg), microcrystalline cellulose (10 mg), carboxyvinyl
polymer (10 mg) , hydrogenated oil (80 mg) and lactose (20 mg)
for a drug releasing layer; and ethyl cellulose (120 mg),
carboxyvinyl polymer (15 mg) and polyethylene oxide (15 mg)
for a gastric resident layer per tablet.
77
CA 02673485 2009-06-19
[0176]
(Dissolution test)
Small diameter (JP first fluid): 7.27 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid) : 7.30 mm, maximum load: > 10000
g
[0177]
Example 19
According to Example 1, there was prepared a gastric
retentive preparation in three-layered (where a gastric
resident layer is a middle layer) and irregular shaped tablets
each having 14 mm large diameter and 7 mm small diameter and
containing: levodopa (100 mg), carbidopa (25 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 75
mg), microcrystalline cellulose (50 mg) and anhydrous citric
acid (12.5 mg) for a sustained release drug releasing layer;
methacrylic acid-ethyl acrylate copolymer (120 mg) and
hydroxypropyl methyl cellulose 2208 (30 mg) for a gastric
resident layer; and levodopa (100 mg) , carbidopa (25 mg) , low
substituted hydroxypropyl cellulose (L-HPC LH-11, 7.5 mg),
microcrystalline cellulose (15 mg) and anhydrous citric acid
(12.5 mg) for an immediately release drug-releasing layer per
tablet.
[0178]
Example 20
According to Example 19, there was prepared a gastric
78
CA 02673485 2009-06-19
retentive preparation in three-layered and irregular shaped
tablets each having 14 mm large diameter and 7 mm small diameter
and containing: levodopa (140 mg), carbidopa (35 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 87.5
mg), microcrystalline cellulose (37.5 mg) and anhydrous citric
acid (17.5 mg) for a sustained release drug releasing layer;
methacrylic acid-ethyl acrylate copolymer (120 mg) and
hydroxypropyl methyl cellulose 2208 (30 mg) for a gastric
resident layer; and levodopa (60 mg), carbidopa (15 mg), low
substituted hydroxypropyl cellulose (L-HPC LH-11, 4.5 mg),
microcrystalline cellulose (9 mg) and anhydrous citric acid
(7.5 mg) for an immediately release drug-releasing layer per
tablet.
[0179]
Example 21
According to Example 19, there was prepared a gastric
retentive preparation in three-layered and irregular shaped
tablets each having 14 mm large diameter and 7 mm small diameter
and containing: levodopa (180 mg), carbidopa (45 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 100
mg), microcrystalline cellulose (25 mg) and anhydrous citric
acid (22.5 mg) for a sustained release drug releasing layer;
methacrylic acid-ethyl acrylate copolymer (120 mg) and
hydroxypropyl methyl cellulose 2208 (30 mg) for a gastric
resident layer; and levodopa (20 mg), carbidopa (5 mg), low
substituted hydroxypropyl cellulose (L-HPC LH-11, 1.5 mg),
microcrystalline cellulose (3 mg) and anhydrous citric acid
79
CA 02673485 2009-06-19
(2.5 mg) for an immediately release drug-releasing layer per
tablet.
[0180]
Example 22
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (100 mg)
for the gastric resident layer.
[0181]
(Dissolution test)
Small diameter (JP first fluid): 8.05 mm
Dissolution time (JP second fluid): 3 hours
(Strength test)
Small diameter (JP first fluid) : 8. 09 mm, maximum load: > 10000
g
[0182]
Example 23
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and milled hydroxypropyl methyl cellulose phthalate 200731
(HPMCPHP-55, 80 mg) and hydroxypropyl cellulose (20 mg) for
CA 02673485 2009-06-19
the gastric resident layer.
[0183]
(Dissolution test)
Small diameter (JP first fluid): 8.67 mm
Dissolution time (JP second fluid): 3 hours
(Strength test)
Small diameter (JP first fluid): 7.87 mm, maximum load: 6080
g
[0184]
Example 24
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and milled cellulose acetate phthalate (80 mg) and
hydroxypropyl cellulose (20 mg) for the gastric resident layer.
[0185]
(Dissolution test)
Small diameter (JP first fluid): 8.39 mm
Dissolution time (JP second fluid): 3 hours
(Strength test)
Small diameter (JP first fluid) : 8.06 mm, maximum load: > 10000
g
[0186]
Example 25
According to Example 1, flat and circular tablets of
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CA 02673485 2009-06-19
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydrogenated oil (75 mg), polyethylene oxide (Polyox WSR
N-750, 5 mg), carmellose calcium (ECG-505, 5 mg) and
microcrystalline cellulose (Ceolus PH101, 15 mg) for the
gastric resident layer.
[0187]
(Dissolution test)
Small diameter (JP first fluid): 8.16 mm
Dissolution time (JP second fluid): 8 hours
(Strength test)
Small diameter (JP first fluid): 7.62 mm, maximum load: 8885
g
[0188]
Example'26
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and stearic acid (75 mg), carboxyvinyl polymer (5 mg),
polyethylene oxide (Polyox WSR N-750, 5 mg) and anhydrous
calcium hydrogen phosphate (15 mg) for the gastric resident
layer.
[0189]
82
CA 02673485 2009-06-19
(Dissolution test)
Small diameter (JP first fluid): 8.72 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid): 7.48 mm, maximum load: 6030
g
[0190]
Example 27
According to Example 1, irregular shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg) , carbidopa (50 mg) , entacapone (200 mg) and
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 100
mg) for the sustained release drug releasing layer; and
methacrylic acid-ethyl acrylate copolymer (120 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 30
mg) for the gastric resident layer.
[0191]
Example 28
According to Example 1, irregular shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200 mg), carbidopa (50 mg), tolcapone (200 mg) and
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 100
mg) for the sustained release drug releasing layer; and
methacrylic acid-ethyl acrylate copolymer (120 mg) and
hydroxypropyl methyl cellulose 2208 (Metolose 90SH 100SR, 30
83
CA 02673485 2009-06-19
mg) for the gastric resident layer.
[0192]
Example 29
According to Example 1, irregular shaped tablets of
gastric retentive preparation having a large diameter of 14
mm and a small diameter of 7 mm were prepared, each containing:
levodopa (200mg),benserazide (50 mg) and hydroxypropyl methyl
cellulose 2208 (Methocel K100M P CR, 100 mg) for the sustained
release drug releasing layer; and methacrylic acid-ethyl
acrylate copolymer (120 mg) and hydroxypropyl methyl cellulose
2208 (Metolose 90SH 100SR, 30 mg) for the gastric resident
layer.
[0193]
Example 30
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydroxypropyl methyl cellulose acetate succinate (60 mg),
hydroxypropyl cellulose (5 mg) and lactose (35 mg) for the
gastric resident layer.
[0194]
(Dissolution test)
Small diameter (JP first fluid): 8.40 mm
Dissolution time (JP second fluid): 1.5 hours
(Strength test)
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CA 02673485 2009-06-19
Small diameter (JP first fluid) : 8.28 mm, maximum load: 8870
g
[0195]
Example 31
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and polyethylene oxide (Polyox WSR-N 750, 5 mg), sodium
carboxymethyl starch (Primojel, 5 mg) and lactose (5 mg) for
the gastric resident layer.
[0196]
(Dissolution test)
Small diameter (JP first fluid): 8.14 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid) : 7.88 mm, maximum load: > 10000
g
[0197]
Example 32
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydrogenated oil (85 mg) , xanthan gum (5 mg) , polyethylene
CA 02673485 2009-06-19
oxide (Polyox WSR-N 750, 5 mg) and anhydrous calcium hydrogen
phosphate (5 mg) for the gastric resident layer.
[0198]
(Dissolution test)
Small diameter (JP first fluid): 8.06 mm
Dissolution time (JP second fluid): 5 hours
(Strength test)
Small diameter (JP first fluid): 7.00 mm, maximum load: 6530
g
[0199]
Example 33
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (Eudragit
L100-55, 70 mg), povidone (Plasdone K29/32, 10 mg), methyl
cellulose (SM-4, 10 mg) and mannitol (10 mg) for the gastric
resident layer.
[0200]
(Dissolution test)
Small diameter (JP first fluid): 9.16 mm
Dissolution time (JP second fluid): 3 hours
(Strength test)
Small diameter (JP first fluid) : 8.77 mm, maximum load: > 10000
g
86
CA 02673485 2009-06-19
[0201]
Example 34
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and methacrylic acid-ethyl acrylate copolymer (Eudragit
L100-55, 70 mg) , povidone (Plasdone K29/32, 10 mg), Macrogol
6000 (10 mg) and mannitol (10 mg) for the gastric resident
layer.
[0202]
(Dissolution test)
Small diameter (JP first fluid): 9.96 mm
Dissolution time (JP second fluid): 2 hours
(Strength test)
Small diameter (JP first fluid): 9.09 mm, maximum load: 6210
g
[0203]
Example 35
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydrogenated oil (50 mg), stearyl alcohol (30 mg),
carboxyvinyl polymer (5 mg), povidone (Plasdone K29/32, 5 mg),
87
CA 02673485 2009-06-19
methyl cellulose (SM-4, 5 mg) and mannitol (5 mg) for the
gastric resident layer.
[0204]
(Dissolution test)
Small diameter (JP first fluid): 8.24 mm
Dissolution time (JP second fluid): 9 hours
(Strength test)
Small diameter (JP first fluid) : 8.18 mm, maximum load: > 10000
g
[0205]
Example 36
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydrogenated oil (50mg), tetraglycerolpentaester (PS-3S,
30 mg) , carboxyvinyl polymer (5 mg) , povidone (Plasdone K29/32,
5 mg) , Macrogol 6000 (5 mg) and mannitol (5 mg) for the gastric
resident layer.
[0206]
(Dissolution test)
Small diameter (JP first fluid): 8.15 mm
Dissolution time (JP second fluid): 6 hours
(Strength test)
Small diameter (JP first fluid) : 8.09 mm, maximum load: > 10000
g
88
CA 02673485 2009-06-19
[0207]
Example 37
According to Example 1, flat and circular tablets of
gastric retentive preparation having a diameter of 8 mm were
prepared, each containing: levodopa (100 mg), carbidopa (25
mg) and hydroxypropyl methyl cellulose 2208 (Methocel K100M
P CR, 50 mg) for the sustained release drug releasing layer;
and hydrogenated oil (60 mg), carboxyvinyl polymer (5 mg),
povidone (Plasdone K29/32, 5 mg) and mannitol (30 mg) for the
gastric resident layer.
[0208]
(Dissolution test)
Small diameter (JP first fluid): 8.10 mm
Dissolution time (JP second fluid): 6 hours
(Strength test)
Small diameter (JP first fluid): 8.07 mm, maximum load: 9100
g
[0209]
Comparative Example 1
Levodopa (1600 mg) and carbidopa (400 mg) were dissolved
in the JP first fluid (400 mL) to prepare a levodopa-carbidopa
solution.
[0210]
Comparative Example 2
According to Example 1 except for using an
irregular-shaped die and punch having a large diameter of 17. 5
mm and a small diameter of 7.5 mm, irregular-shaped tablets
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CA 02673485 2009-06-19
of gastric retentive preparation having a large diameter of
17.5 mm and a small diameter of 7.5 mm were prepared, each
containing: levodopa (200 mg), carbidopa (50 mg),
hydroxypropyl methyl cellulose 2208 (Methocel K100M P CR, 100
mg) and microcrystalline cellulose (Ceolus PH 101, 100 mg) for
the sustained release drug releasing layer; and xanthan gum
(180 mg), hydroxypropyl methyl cellulose 2208 (Metolose 90SH
30000F, 157.5 mg), microcrystalline cellulose (76.5 mg) and
guar gum (36 mg) for the gastric resident layer.
[0211]
(Dissolution test)
Small diameter (JP first fluid): 8.38 mm
Large diameter (JP second fluid): 22.14 mm
(Strength test)
Small diameter (JP first fluid) : 7.76 mm, maximum load: 3000
g
[0212]
(Pharmacokinetic test in dogs)
Pharmacokinetic test was conducted in dogs using the
preparations manufactured in Examples and Comparative Example,
a levodopa-carbidopa solution and commercially available
Sinemet CR tablets.
[0213]
CA 02673485 2009-06-19
[Table 1]
Test Preparations Administered Size of Preparation Total Dose
Nos. Levodo a/ Carbido a
1 Example 1 14 mm x 7 mm 200 mg 150 mg
2 Example 2 14 mm x 7 mm 200 mg /50 mg
3 Example 3 14 mm x 7 mm 200 mg 150 mg
4 Example 4 14 mm x 7 mm 200 mg / 50 mg
Examples 4 + 2 (at the same time) 14 mm x 7 mm 400 mg / 100 mg
6 Example 5 17.5 mm x 7.5 mm 200 mg / 50 mg
7 Example 6 17.5 mm x 7.5 mm 200 mg / 50 mg
8 Comp Ex 1 (solution) 200 mg / 50 mg
9 CompEx2 17.5mmx7.5mm 200mg/50mg
Sinemet CR 12.8 mm x 7.2 mm 200 mg I 50 mg
11 Sinemet CR 12.8 mm x 7.2 mm 400 mg /100 mg
ally administered after 6 hrs
[0214]
(Measurement of drug concentrations in blood)
After a test preparation was orally administered to
5 beagles of 30 to 42 months age where one group comprised 2 to
10 beagles, blood was taken and extracted and then
concentration of the drug in plasma was measured by means of
LC-MS/MS. The feeding condition was that beagles were placed
in a cage with free access to water, fasted for 20 hours or
10 more and a feed where 250 g of solid dog food and 50 g of chum
were mixed was given. After 30 minutes from the feeding, the
test preparation and 20 ml of water were administered. Taking
of the blood was conducted in an amount of 1 mL from vein of
brachial periodically using a syringe containing heparin. As
to a stabilizer, EGTA (0.5 mg) and reduced glutathione (0.3
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CA 02673485 2009-06-19
mg) were suspended in a mixture of 50% of N, N-dimethylacetamide
and 50% of distilled water and previously placed in tubes for
total blood and for plasma.
An extracting operation was as follows. Thus, firstly,
0. 025 mL of 2N aqueous solution of hydrochloric acid was added
to a tube. After that, 0.1 mL of internal standard substance
(a solution of 100 ng/mL metformin in acetonitrile) was added
to 0.1 mL of plasma prepared hereinabove and 0.3 mL of
acetonitrile was added thereto to remove protein. After
centrifugal separation, 0.005 mL of the resulting supernatant
liquid was injected into LC-MS/MS. Measurement was conducted
using LC-MS/MS under the following condition. A calibration
curve was prepared by conducting the same operation as above
for a preparation where internal standard substance (a solution
of 100 ng/mL metforminin acetonitrile), levodopa and carbidopa
were appropriately added to 0.1 mL of a blank plasma.
[0215]
LC condition was as follows.
Apparatus: Agilent 1100
Column: Cadenza C18, 3 m, 4.6 x 50 mm
Mobile phase: Aqueous solution of 10 mM ammonium acetate (pH
4.5) (A) / acetonitrile (B)
[0216]
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CA 02673485 2009-06-19
[Table 2]
(minute(s)) A (o) B (%)
0.0 90 10
3.0 90 10
4.0 10 90
7.0 10 90
7.1 90 10
12.0 90 10
Column temperature: 40 C
Flow rate: 0.5 mL/min
MS/MS conditions
Apparatus: API-4000
Ionizing method: ESI (positive) (Trubo Ion Spray)
[0217]
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CA 02673485 2009-06-19
[Table 3]
Test N(numbers Cmax Tmax AUC (O-X) MRT
Nos. Preparation Administered of beagles) (nglml) (hr) (ngxhr/ml) (hr)
mean SD mean SD mean SD mean SD
1 Example 1 9 1615 866 3.4 1.8 10468 2852 5.9 1.3
2 Example 2 2 1622 4.0 10118 4.9
3 Example 3 3 1687 433 6.8 3.0 11122 2072 5.9 1.2
4 Example 4 6 1088 73 5.2 2.7 8084 705 7.1 1.1
Example 4
(Two tablets were administered 6 4025 1111 5.0 3.0 29661 4960 6.6 0.9
at the same time)
6 Example 5 3 981 120 6.0 2.0 6617 995 5.4 1.2
7 Example 6 3 984 113 4.7 3.1 6354 662 6.1 2.0
8 Comp Ex 1 6 8116 8073 0.8 0.4 15453 4822 2.3 0.8
9 Comp Ex 2 3 992 272 8.0t0.0 6816 612 6.2 0.2
Sinemet CR 10 3727 1951 1.5 1.1 10564 3748 2.8 0.5
Sinemet CR
11 (Additionally administered after 8 6105 1793 6.6 3.9 30716 7528 6.2
0.9
6 hours)
[ 0218 ]
Cmax is the maximum concentration in blood; Tmax is the
time until reaching the maximum concentration in blood; AUC
5 is the area under the curve for drug concentration in blood
vs. time; and MRT is mean retention time.
[0219]
Mean retention time is usually an index for the
persistence of the concentration in blood and it means that,
10 when the mean retention time is longer, function as a sustained
release preparation is higher.
[0220]
As mentioned above, the preparation according to the
present invention maintains the concentration of levodopa in
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CA 02673485 2009-06-19
blood longer than Sinemet CR tablet does showing that levodopa
is able to achieve a sustained release in the stomach (Fig.
2) In the group where Sinemet CR tablets were additionally
administered after six hours, concentration in blood was unable
to be kept constantly as compared with the group where the
preparation of Example 4 was administered in two tablets at
the same time (Fig. 3) . Therefore, the preparation according
to the present invention is a preparation which keeps the
changes in concentration in blood constantly as compared with
Sinemet CR tablets of a short-time releasing type and is a
preparation which is able to overcome the problems in the
levodopa preparations which are available at present. From
the above result, the gastric retentive preparation according
to the present invention is a preparation which is able to
maximize the effect of levodopa.
[0221]
(dissolution test)
In accordance with a paddle method of a dissolution test
method stipulated by the Japanese Pharmacopoeia, a test
preparation was placed in a sinker, immersed in the JP first
fluid (900 mL) and stirred at 37 C for 24 hours at a paddle
speed of 100 rpm. The test solution was sampled periodically
and the released rate of the drug was measured by an HPLC under
the following condition.
[0222]
Apparatus: Shimadzu Prominence
Column: Inertsil ODS-3, 5 m, 4.6 x 150 mm
CA 02673485 2009-06-19
Column temperature: 25 C
Mobile phase: 20 mM potassium dihydrogen phosphate (pH = 2. 3)
acetonitrile (= 96:4)
Flow rate: 1 mL/min
Detector: UV of 280 nm
[0223]
It is concluded from the result shown in Figs. 4 to 23
that the preparation according to the present invention is a
preparation which persistently releases levodopa and/or
carbidopa in an almost constant rate.
[Industrial Applicability]
[0224]
A gastric retentive preparation according to the present
invention has a sufficient gastric residence time, has a size
that enables easy ingestion and can disintegrate quickly after
expelled from the stomach. The gastric retenti.ve preparation
is therefore useful as a sustained release preparation and is
also a levodopa preparation which is easily prepared in
industry.
96
